KR20200088857A - Treatment of purulent puritis with IL-17 antagonists - Google Patents

Abstract

The present invention relates to a method of treating purulent cholineitis (HS) using an IL-17 antagonist, for example secukinumab. IL-17 antagonists for treating HS patients, such as IL-17 antibodies, such as secukinumab, and medicaments, dosing regimens, pharmaceutical agents, dosage forms and kits for use in the disclosed uses and methods are also described herein. Is disclosed.

Description

Treatment of purulent puritis with IL-17 antagonists

Related applications

This application claims the priority of U.S. Provisional Application No. 62/588687, filed November 20, 2017, the entirety of which is incorporated herein by reference.

Technology field

The present invention relates to a method of treating purulent vasculitis (Hidradenitis suppurativa) using an IL-17 antagonist, for example secukinumab.

Purulent pyelitis (HS) (also called translocation acne or Verneuil disease) is a chronic, recurrent inflammatory disease characterized by deep nodules, pus pockets, and abscesses, which occur in the armpits, groin, breast folds, and anal genital areas. Leads to fibrosis. (Revuz and Jemec (2016) Dermatol Clin 34:1-5; Jemec GB. (2012) N Engl J Med 366:158-64). This is associated with substantial pain and metabolic disorders, co-morbidities including psychiatric disorders and autoimmune disorders, and an increased risk of skin cancer. (Revuz (2016); Shlyankevich et al. (2014) J Am Acad Dermatol 71:1144-50; Kohorst et al (2015) J Am Acad Dermatol 73:S27-35; Wolkenstein et al. (2007) J Am Acad Dermatol 56:621-3).

The reported prevalence of HS is less than 1% to 4% of the population. (Shlyankevich et al. (2014); Cosmatos et al. (2013) J Am Acad Dermatol 68:412-9; Davis et al. (2015) Skin Appendage Disord 1:65-73; Revuz et al. (2008) J Am Acad Dermatol 59:596-601; McMillan K. (2014) Am J Epidemiol 179:1477-83; Garg et al. (2017) JAMA Dermatol; Jemec et al. (1996) J Am Acad Dermatol 35:191-4 ). However, since HS is under-diagnosed and estimates fluctuate with study design, population, and geographic location, the true prevalence is difficult to ascertain. (Miller et al. (2016) Dermatol Clin 34:7-16). Although the National Institutes of Health (NIH) did not classify HS as a rare disease, experts generally believe that the prevalence of the disease is less than 1% of the United States (US) population. (Cosmatos et al. (2013); Genetic and Rare Diseases Information Center.National Institutes of Health.Hidradenitis suppurativa. //rarediseases.info.nih.gov/diseases/6658/hidradenitis-suppurativa available March 20, 2017 One connection; Gulliver et al. (2016) Rev Endocr Metab Disord 17:343-51).

Current treatments for HS consist of topical and/or systemic antibiotics, hormonal interventions, analgesics and in some cases immunosuppressants, tumor necrosis factor (TNF) inhibitor monoclonal antibody adalimumab and surgical resection. (Gulliver et al. (2016); Zouboulis et al. (2015) J Eur Acad Dermatol Venereol 29:619-4414-16; Kimball et al. (2016) N Engl J Med 375:422-34). However, symptom control and lesion resolution are inconsistent during treatment. The recurrence rate is high after discontinuation of antibiotic treatment, and long-term treatment with retinoids creates teratogenic concerns. In addition, the effectiveness of inflammatory drugs such as dapsone, fumarate and cyclosporine is based on a few case studies with various results. As a result of these inconsistent results, and the severity of HS disease, HS patients use health care in a more expensive environment (eg, emergency room and inpatient care) more often than patients with other chronic inflammatory skin diseases (Khalsa et. al. (2016) J Am Acad Dermatol 73:609-14; Kirby et al. (2014) JAMA Dermatol 150:937-44). Since there is no medical cure for HS, and the disease is physically and psychologically debilitating, there is a clear unmet need to provide safe and long-term effective treatment for HS patients.

Although the pathogenesis of HS is still not fully understood, Van der Zee et al. (2011) and Kelly et al. (2015) show that IL-17, IL-1β and TNF-α expression is enhanced in lesions and peri-lesional skin of HS patients. Matusiak et al. (2017) found that HS patients had increased IL-17 serum levels compared to healthy volunteers and tended to higher IL-17 serum concentrations in patients with more advanced disease. (Van der Zee et al. (2011) Br. Ass. Derm. 164:1292-1298 and Kelly et al. (2015) Br. J. Dermatol. 173(6):1431-9; Matusiak et al. (2017) ) J. Am. Acad. Dermatol. 76(4):670-675). Conversely, Block et al. (2015) found that there was no substantial difference in serum concentrations of IL-2R, TNF-α, IL-17A and IL-17F between HS patients and healthy controls, and Banjeree et al. (2017) It has been found that there is no substantial difference in proinflammatory cytokines, including, for example, TNF-α, IL-1β, IL-1α, IL-17A in HS wound effluent for specimens obtained from patients. (Block et al. (2015) Br. J. Dermatol. 174:839-846; Banjeree et al. (2017) Immunological Investigations 46:149-158). In addition, during the open-label psoriasis study, the IL-17 antagonist, Ixezizumab, triggered three distinct HS flares in the same patient. (Gordon et al. (2014) J. Am. Acad. Dermatol. 71(6):1176-82; Gordon et al. 72 ^nd Annu.Meet Am Acad Dermatol (AAD) (March 21-25, Denver) 2014, Abst P7617). Therefore, it is not clear whether IL-17 dysregulation is associated with HS pathogenesis (ie disease drivers) or simply results from inflammation and/or wounds caused by other triggers (ie disease passengers).

Secukinumab is a recombinant high-affinity, fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody of the IgG ₁ /kappa isotype. Secukinumab (see, eg, WO 2006/013107 and WO 2007/117749) has a very high affinity for IL-17, i.e. about 100-200 pM K _D and about 0.67 nM human IL-17A Has an IC ₅₀ of about 0.4 nM for in vitro neutralization of its biological activity. Thus, secukinumab inhibits the antigen in a molar ratio of about 1:1. This high binding affinity makes secukinumab antibodies particularly suitable for therapeutic applications. Moreover, secuquinumab has a long half-life, ie about 4 weeks, which allows for extended periods between dosing, which are extremely exceptional properties when treating chronic lifelong disorders such as HS.

There are two case reports of secukinumab treatment in HS patients. Schuch et al. (2017) used secukinumab at a dose of 300 mg SC weekly (0 days, 7 days, 14 days, 21 days and 28 days) for 1 month, followed by severe resistance by injection at 4 week intervals It has been reported to treat HS (Schuch et al. (2017) Acta Derm Venereol. 2018 Jan 12; 98(1):151-152). Similarly, Thorlacius et al. (2017) reported treating HS patients with Hurley III stage lesions using 300 mg of secukinumab SC every week for the first 4 weeks, followed by 300 mg SC every 4 weeks. (Thorlacius et al. (2017) Br. J. Dermatol doi: 10.1111/bjd.15769. [Epub ahead of print]). However, in Thorlacius et al. (2017), improvement in the number of boils, pain VAS, and pain/useful/handicap VAS reported by the patient was not well reproduced at the score reported by the doctor, and the quality of life of the patient after initiation of treatment was There was no improvement as reflected in the patient's lack of change in the Dermatology Life Quality Index (DLQI). Moreover, neither Schuch et al. (2017) nor Thorlacius et al. (2017) reported whether the treatment used provided a sustained response or whether the response was lost over time.

We now treat HS patients with secukinumab (and similar IL-17 antagonists, eg, similar IL-17 antibodies or antigen-binding fragments thereof) that provide a significantly effective and sustained response to HS patients. The regimen was devised. As a method of treating HS, a dose of about 300 mg to about 450 mg IL-17 antibody or antigen-binding thereof at a dose of about 300 mg per week for 0 weeks, 1 week, 2 weeks and 3 weeks to a patient in need thereof Fragments are administered subcutaneously (SC), followed by

a) starting every 4 weeks every month (every 4 weeks); or

b) Starts for 4 weeks every other week (every 2 weeks)

Disclosed herein is a method comprising administering SC at a dose of about 300 mg to about 450 mg.

In some embodiments of the disclosed uses, methods and kits, the IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127 , An IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of human IL-17, including Val128, His129; b) an IL-17 antibody or antigen-binding fragment thereof that binds to the epitope of human IL-17, including Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer with two mature human IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88 in one chain , Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains); d) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer with two mature human IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88 in one chain , Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, the IL-17 antibody or antigen-binding fragment thereof has a K _D of about 100 to 200 pM, and the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 23 days to about 35 days); e) IL-17 antibody that binds to the epitope of the IL-17 homodimer with two mature IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, in one chain) Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, IL-17 antibody has a K _D of about 100 as measured by a biosensor system (e.g. BIACORE). ~ 200 pM, IL-17 antibody has an in vivo half-life of about 23 days to about 30 days); And f) i) an immunoglobulin heavy chain variable domain (V _H ) comprising the amino acid sequence set forth in SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V _L ) comprising the amino acid sequence set forth in SEQ ID NO: 10; iii) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and an immunoglobulin V _L domain comprising the amino acid sequence set forth in SEQ ID NO: 10; iv) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; v) an immunoglobulin V _L domain comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; vi) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; vii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; viii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15; Or xi) an IL-17 antibody or antigen-binding fragment thereof comprising an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

In a preferred embodiment, the IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is about 300 mg to about 450 mg, for example about 300 mg or about 450 mg ( For example, 300 mg or 450 mg) is administered subcutaneously (SC). In some embodiments, an IL-17 antagonist (eg, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered using an induction regime, followed by a maintenance regime. In some embodiments, the induction regime comprises weekly administration, and the maintenance regime comprises administration every 2 weeks or every 4 weeks. In some embodiments, an IL-17 antagonist (eg, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is at week 0, week 1, week 2, week 3 and week 4, followed by SC is administered at a dose of about 300 mg every 2 weeks, for example 300 mg. In some embodiments, the IL-17 antagonist (eg, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is at week 0, week 1, week 2, week 3 and week 4, followed by SC is administered at a dose of about 300 mg every 4 weeks, for example 300 mg. In some embodiments, the IL-17 antagonist (eg, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is at week 0, week 1, week 2, week 3 and week 4, followed by SC is administered at a dose of about 450 mg (eg, 450 mg) every 4 weeks (monthly).

1 shows the rate of HS-PGA response by treatment-Period 1 (PD analysis set 1; n/N) for the CJM112 experiment of Example 1. N = number of patients in PD analysis set 1. n = number of HS-PGA responders. The HS-PGA responders in Period 1 are study participants with an initial HS-PGA score of at least 3 at baseline (1 day, inclusion criteria) and a reduction of at least 2 points. Subjects who have discontinued and have not reached the end point of the first treatment period will be considered non-responder if the cause of the discontinuation is a side effect or local tolerance failure that is believed to be related to the trial treatment by the investigator. The discontinued subject did not do so for any of these causes. Post-baseline missing values resulting from missing assessments at any given time point up to 16 weeks are entered using the last observation carried forward procedure (LOCF) for primary efficacy analysis.
FIG. 2 shows the secukinumab PASI 90 response rates simulated up to 52 weeks for different secukinumab regimens in subjects weighing 90 kg or more. The curve shows the median of the simulated response rate, and the surrounding shaded area provides a 95% prediction interval for the simulation.
3A shows two secukinumab dosing regimens with the same loading dose, but different maintenance doses (ie every 2 weeks (Q2wks) or every 4 weeks (Q4wks).
3B shows two proposed secuquinumab HS clinical trials, one using a combination antibiotic and the other without a combination antibiotic.
FIG. 4 shows the predicted secukinumab systemic exposure by 2 and 4 week dosing intervals during maintenance at the 300 mg dose level.
FIG. 5 shows the simulated PASI 90 response rate and corresponding lowest concentration (mcg/mL) for secukinumab achieved using 300 mg Q2W and 300 mg Q4W based on patients weighing greater than or less than 90 kg.

As used herein, IL-17 refers to interleukin-17A (IL-17A).

The term “comprising” also encompasses “consisting of,” for example, a composition “comprising” of X may consist exclusively of X, or may include any further, such as X + Y. have.

Unless specifically stated otherwise or clear from context, as used herein, the term “about” with respect to numerical values is understood to be within general tolerances in the art, such as within two standard deviations of the mean. . Thus, “about” means ± 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.05%, or 0.01% of the stated value, Preferably within ± 10% of the stated value. When used in front of a number range or list of numbers, the term "about" applies to each number in the series, for example the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or For example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4."

The word "substantially" does not exclude "completely", for example, a composition "substantially free of Y" may be completely free of Y. When necessary, the word "substantially" may be omitted from the definition of the present invention.

The term “antibody” as referred to herein includes naturally occurring and total antibodies. Naturally occurring "antibodies" are glycoproteins comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as V _H ) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as V _L ) and a light chain constant region. The light chain constant region consists of one domain, CL. The V _H and V _L regions can be further subdivided into regions of hypervariability, called hypervariable regions or complementarity determining regions (CDRs), between which there is a framework region (FR). Preserved areas are interspersed. Each V _H and V _L consists of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody may mediate the binding of immunoglobulins to various cells of the host tissue or immune system (eg, effector cells) and factors comprising the first component of the traditional complement system (C1q). Exemplary antibodies include Secukinumab ( Table 1 ), antibodies XAB4 (US Pat. No. 9,193,788) and Ixequizumab (US Pat. No. 7,838,638), the disclosures of which are incorporated herein by reference in their entirety. .

As used herein, the term “antigen-binding fragment” of an antibody refers to a fragment of an antibody that retains the ability to specifically bind an antigen (eg, IL-17). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include Fab fragments, monovalent fragments consisting of the V _L , V _H , CL and CH1 domains; An F(ab) ₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragment consisting of V _H and CH1 domains; Fv fragment consisting of the V _L and V _H domains of a single arm of an antibody; A dAb fragment consisting of the V _H domain (Ward et al., 1989 Nature 341:544-546); And isolated CDRs. Exemplary antigen-binding fragments comprise the CDRs of secukinumab, preferably heavy chain CDR3, as set forth in SEQ ID NOs: 1-6 and SEQ ID NOs: 11-13 ( Table 1 ). Moreover, the two domains of the Fv fragments, V _L and V _H , are encoded by separate genes, but they can be linked using recombinant methods by synthetic linkers that allow them to be made into a single protein chain, this single protein. The V _L and V _H regions in the chain are paired as monovalent molecules (known as short chain Fvs (scFvs); see e.g. Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc . Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antibody”. Single chain antibodies and antigen-binding moieties are obtained using conventional techniques known to those skilled in the art.

As used herein, “isolated antibody” refers to an antibody that is substantially free of other antibodies with different antigen specificities (eg, an isolated antibody that specifically binds IL-17 is other than IL-17. Substantially no antibodies that specifically bind the antigen). As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to the preparation of antibody molecules of a single molecule composition. As used herein, the term “human antibody” is intended to include antibodies in which both the framework and CDR regions have variable regions derived from sequences of human origin. “Human antibodies” need not be made by humans, human tissues or human cells. Human antibodies of the invention are amino acid residues that are not encoded by the human sequence (e.g., by random or site specific mutagenesis in vitro, by addition of N-nucleotides at the junction in vivo during recombination of the antibody gene, or Mutations introduced by somatic cell mutations in vivo. In some embodiments of the disclosed processes and compositions, the IL-17 antibody is a human antibody, isolated antibody, and/or monoclonal antibody.

The term “IL-17” refers to IL-17A, previously known as CTLA8, and wild-type IL-17A, polymorphic variants of IL-17A, and IL- from various species (eg, human, mouse, and monkey) 17A functional equivalent. The functional equivalent of IL-17A according to the invention is preferably at least about 65%, 75%, 85%, 95%, 96%, 97%, with wild type IL-17A (e.g., human IL-17A), It has a 98% or even 99% overall sequence identity and substantially retains the ability to induce IL-6 production by human dermal fibroblasts.

The term “K _D ”is intended to refer to the rate of dissociation of a particular antibody-antigen interaction. As used herein, the term “K _D ”is intended to refer to the dissociation constant, which is obtained from the ratio of K _d to K _a (ie, K _d /K _a ), molar concentration (M) It is indicated by. K _D values for antibodies can be determined using methods established in the art. The preferred method for determining the K _D of an antibody is carried out using surface plasmon resonance or using a biosensor system, such as a Biacore® system. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, eg secukinumab, binds human IL-17 with a K _D of about 100-250 pM.

The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody “arm” interacts with the antigen at several sites through weak, non-covalent forces; The more interactions, the stronger the affinity. Standard assays for evaluating the binding affinity of antibodies to IL-17 of various species, including, for example, ELISA, Western blot, and RIA, are known in the art. The binding kinetics of the antibody (eg, binding affinity) can also be assessed by assays known in the art, eg, using Biacore® analysis.

Antibodies that “inhibit” one or more of these functional properties of IL-17 (eg, biochemical, immunochemical, cellular, physiological or other biological activity, etc.) as determined in accordance with the methodology known in the art and described herein are It will be understood that this is associated with a statistically significant decrease in specific activity compared to what appears in the absence of the antibody (or when a control antibody of unrelated specificity is present). Antibodies that inhibit IL-17 activity affect statistically significant reductions, e.g., by at least about 10%, at least 50%, 80%, or 90% of the measured parameters, and certain embodiments of the disclosed methods and compositions In, the IL-17 antibody used can inhibit IL-17 functional activity by more than 95%, 98% or 99%.

“Inhibit IL-6” as used herein refers to an IL-17 antibody or antigen-binding fragment thereof (eg, secukinumab) that reduces IL-6 production from primary human dermal fibroblasts. Refers to ability. The production of IL-6 in primary human (dermal) fibroblasts is IL-17 dependent (Hwang et al., (2004) Arthritis Res Ther; 6:R120-128). In short, human dermal fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of IL-17 binding molecule or human IL-17 receptor with Fc portion. Chimeric anti -CD25 antibody Simulect ^® (Basil rigs during Thank) it may be used conveniently as a negative control. The supernatant was taken after 16 hours of stimulation and evaluated for IL-6 by ELISA. IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab, are typically administered as IC ₅₀ for inhibition of IL-6 production when tested as described above (in the presence of 1 nM human IL-17). 50 nM or less (eg, about 0.01 to about 50 nM), ie, the inhibitory activity is measured in IL-6 production induced by hu-IL-17 in human dermal fibroblasts. In some embodiments of the disclosed methods and compositions, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, and a functional derivative thereof, has an IC ₅₀ medicament for inhibition of IL-6 production as defined above. 20 nM or less, more preferably about 10 nM or less, more preferably about 5 nM or less, more preferably about 2 nM or less, more preferably about 1 nM or less.

The term “derivative”, unless indicated otherwise, IL-17 antibody or antigen-binding fragment thereof, eg, a defined sequence (eg, variable domain) of secukinumab according to the invention Of, amino acid sequence variants, and covalent modifications (eg, pegylation, deamination, hydroxylation, phosphorylation, methylation, etc.). "Functional derivative" includes molecules having quantitative biological activity common to the disclosed IL-17 antibodies. Functional derivatives include fragments and peptide analogs of IL-17 antibodies as disclosed herein. Fragments include, for example, regions within the sequence of a polypeptide according to the invention of a defined sequence. The functional derivatives of IL-17 antibodies disclosed herein (eg, functional derivatives of secukinumab) are preferably the V _H and/or V _L sequences of IL-17 antibodies disclosed herein and antigen-binding fragments thereof (eg For example, a human having a total sequence identity of at least about 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% with a V _H and/or V _L sequence in Table 1 ), V _H and/or V _L domains that substantially retain the ability to bind to IL-17 or inhibit IL-6 production, eg, of IL-17 induced human dermal fibroblasts.

The phrase “substantially identical” indicates that the related amino acid or nucleotide sequence (eg, V _H or V _L domain) is identical or insignificant difference compared to a particular reference sequence (eg, through conserved amino acid substitutions). It means to have. Significant differences include minor amino acid changes in the 5 amino acid sequence of a defined region (eg, V _H or V _L domain), such as 1 or 2 substitutions. In the case of antibodies, the second antibody has the same specificity and has at least 50% of its affinity. Sequences that are substantially identical to the sequences disclosed herein (eg, at least about 85% sequence identity) are also part of the present application. In some embodiments, the sequence identity of the derivative IL-17 antibody (e.g., a derivative of secukinumab, e.g., secukinumab biosimilar antibody) is at least about 90% relative to the disclosed sequence, e.g., 90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.

“Identity” with respect to natural polypeptides and functional derivatives thereof is equivalent to aligning the sequences to achieve maximum percentage identity and introducing gaps if necessary, without considering any conservative substitutions as part of sequence identity Is defined herein as the percentage of amino acid residues in the candidate sequence that are identical to the residues of the natural polypeptide. N-terminal or C-terminal extension and insertion should not be construed as reducing identity. Methods and computer programs for alignment are known. Percent identity is a standard alignment algorithm, see, for example, Altshul et al. ((1990) J. Mol. Biol., 215: 403 410); Basic Local Alignment Search Tool (BLAST); See Needleman et al. ((1970) J. Mol. Biol., 48: 444 453)]; Or Meyers et al. ((1988) Comput. Appl. Biosci., 4: 11 17). The series of parameters can be a Blossom 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4 and a frameshift gap penalty of 5. Percent identity between two amino acid or nucleotide sequences is incorporated into the ALIGN program (version 2.0) using the PAM120 weighted residue table, gap length penalty 12 and gap penalty 4 [E. Meyers and W. Miller ((1989) CABIOS, 4:11-17).

“Amino acid(s)” refers to all naturally occurring L-α-amino acids, for example, and includes D-amino acids. The phrase “amino acid sequence variant” refers to a molecule with a slight difference in its amino acid sequence compared to the sequence according to the invention. Amino acid sequence variants of an antibody according to the invention, for example of a defined sequence, still have the ability to bind to human IL-17 or inhibit IL-6 production of, for example, IL-17 induced human dermal fibroblasts . Amino acid sequence variants include substitutional variants (at least one amino acid residue is removed from the polypeptide according to the present invention, and different amino acids are inserted instead at the same position), insertional variants (amino acids at specific positions in the polypeptide according to the present invention And one or more amino acids inserted immediately adjacent to) and deletion variants (one or more amino acids removed from the polypeptide according to the present invention).

The term "pharmaceutically acceptable" means a non-toxic substance that does not interfere with the effectiveness of the biological activity of the active ingredient(s).

The term “administering” in connection with a compound, eg, an IL-17 binding molecule or other substance, is used to refer to the delivery of the compound to a patient by any route.

As used herein, a “therapeutically effective amount” treats or prevents a disorder or recurrent disorder, prevents its onset, cures or delays it, reduces its severity, or at least one symptom thereof. Effective IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 binding molecules) when administered in single or multiple doses to a patient (e.g., a human) to alleviate or prolong patient survival beyond what is expected in the absence of such treatment For example, refers to the amount of an IL-17 antibody or antigen-binding fragment thereof, eg secukinumab) or an IL-17 receptor binding molecule (eg, IL-17 antibody or antigen-binding fragment thereof). This term refers to that component alone when applied to an individual active ingredient administered alone (eg, an IL-17 antagonist, eg secukinumab). The term when applied to a combination, whether administered in combination, continuously or simultaneously, refers to the combined amount of active ingredient that produces a therapeutic effect.

The term “treatment” or “treat” herein refers to a subject's occurrence of a particular disease (eg, HS), symptoms associated with the disease (eg, HS), or the development of a disease (eg, HS). When the child has a predisposition (if applicable), the purpose is to cure the disease (if applicable), delay its onset, reduce its severity, relieve or alleviate one or more symptoms thereof, or IL-17 antibodies according to the present invention to an isolated tissue or cell line from a subject or subject, e.g., three, to improve the disease, reduce or ameliorate predisposition to the occurrence of any associated disease symptom or disease It is defined as the application or administration of cookie numab or exekizumab, or a pharmaceutical composition comprising the anti-IL-17 antibody. The term "treatment" or "treat" includes treating patients suspected of having a disease, and patients diagnosed as having a sick or ill or medical condition, and includes inhibition of clinical recurrence.

As used herein, the phrase “patient population” is used to mean a group of patients. In some embodiments of the disclosed method, an IL-17 antagonist (eg, an IL-17 antibody, such as secukinumab) is used to treat a population of HS patients.

As used herein, the phrases “not previously treated with systemic treatment for HS” and “inexperienced” are systemic preparations for HS, eg methotrexate, cyclosporine, biologics (eg, Ustekinu Refers to HS patients who have not been treated in the past with mob, adalimumab or other TNF alpha inhibitors, etc.). Systemic formulations (i.e., formulations given orally, by injection, etc.) differ from topical formulations (e.g. topical and phototherapy) in that they have a systemic (whole body) effect when delivered to a patient. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient has not been administered systemic treatment for HS in the past.

As used herein, phrases such as “which have been treated in the past with systemic preparations for HS” are used to refer to patients who have experienced HS treatment in the past using systemic preparations. Such patients include patients previously treated with biologics, such as Ustekinumab or TNF-alpha inhibitors, and patients previously treated with non-biological agents such as cyclosporine. In some embodiments of the invention, the patient has been administered systemic preparations for HS in the past. In some embodiments, the patient is administered a systemic agent for HS (e.g., methotrexate, cyclosporine) in the past, but the patient is a systemic biological drug for HS (i.e., drugs produced by living organisms, e.g. antibodies , Receptor decoy, etc.) (e.g., Ustekinumab, Ixezizumab, Broadalumab, TNF alpha inhibitors (etanercept, adalimumab, remicade, etc.), secukinumab, etc.) have not been administered in the past. Did. In this case, the patient is referred to as "inexperienced biological agent". In some embodiments, the patient is "inexperienced biological agent".

As used herein, a term such as “TNF failure” refers to a patient who has had an inadequate response or intolerance to past treatment with a TNF alpha antagonist (eg, etanercept, adalimumab, etc.). . Patients who responded adequately to past treatment with a TNF alpha antagonist (eg, etanercept, adalimumab, etc.) but discontinued due to side effects are said to be “intolerant”. TNF failure is sometimes referred to as a "TNF-IR" patient. In some embodiments, prior to administration of the IL-17 antagonist, the patient is a TNF failure.

As used herein, “selecting” and “selected” in relation to a patient are meant to mean that a particular patient is specifically selected from a larger patient group based on a particular patient with a predetermined criterion (due to the patient). Is used. Similarly, “selectively treating” refers to providing treatment to a patient with a particular disease when that patient is specifically selected from a larger patient group based on a particular patient with a predetermined criterion. Similarly, “selectively administering” refers to administering a drug to a patient specifically selected from a larger patient group based on a specific patient with a predetermined criterion (due to the patient). By selecting, selectively treating, and administering selectively, a patient's personal history (e.g., prior therapeutic intervention, rather than delivering a standard treatment regimen to the patient based solely on the patient's eligibility in a larger group) That personalized treatment is delivered based on, e.g., previous treatment with a biologic, biology (e.g., certain genetic markers), and/or signs (e.g., that do not meet certain diagnostic criteria). Is intended The act of selecting in relation to the method of treatment as used herein does not refer to the accidental treatment of a patient with a specific criterion, but rather to the intentional choice to administer treatment to a patient based on a patient with a specific criterion Refers to. Thus, selective treatment/administration differs from standard treatment/administration of delivering a specific drug to all patients with a particular disease, regardless of its personal history, signs of disease, and/or biology. In some embodiments, the patient is selected for treatment based on having HS. In some embodiments, the patient is selected for treatment based on having been diagnosed with HS for at least 1 year. In some embodiments, the patient is selected for treatment based on having moderate to severe HS. In some embodiments, the patient is selected for treatment based on what has not been previously treated with a systemic HS treatment. In some embodiments, the patient is selected for treatment based on what has not been previously treated with conventional systemic HS therapeutics. In some embodiments, the patient is selected for treatment based on past results of inappropriate responses to conventional systemic HS therapeutics.

As used herein, “conventional systemic therapeutics” refers to antibiotics, steroids, retinoids, hormonal therapeutics, and TNF alpha inhibitors (eg, etanercept, infliximab, adalimumab, etc.).

IL-17 antagonist

Various disclosed processes, kits, uses and methods include IL-17 antagonists such as IL-17 binding molecules (e.g. soluble IL-17 receptor, IL-17 antibody or antigen-binding fragment thereof, e.g. Numab) or IL-17 receptor binding molecule (eg, IL-17 receptor antibody or antigen-binding fragment thereof). In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or antigen-binding fragment thereof.

In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V _H ) comprising hypervariable regions CDR1, CDR2 and CDR3, wherein CDR1 is of SEQ ID NO:1 It has an amino acid sequence, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V _L' ) comprising the hypervariable regions CDR1', CDR2' and CDR3', the CDR1' Has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V _H ) comprising hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein CDR1-x has the amino acid sequence of SEQ ID NO: 11, CDR2-x has the amino acid sequence of SEQ ID NO: 12, and CDR3-x has the amino acid sequence of SEQ ID NO: 13.

In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V _H domain and at least one immunoglobulin V _L domain, wherein a) an immunoglobulin V _H domain (e.g. , In the sequence) i) hypervariable regions CDR1, CDR2 and CDR3 (the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3) ); Or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x (where CDR1-x has the amino acid sequence of SEQ ID NO: 11, wherein CDR2-x has the amino acid sequence of SEQ ID NO: 12, and the CDR3-x Comprises the amino acid sequence of SEQ ID NO: 13); b) the immunoglobulin V _L domain (e.g., in a sequence) hypervariable regions CDR1', CDR2' and CDR3' (where CDR1' has the amino acid sequence of SEQ ID NO: 4, wherein CDR2' is the amino acid of SEQ ID NO: 5) Sequence, wherein the CDR3' has the amino acid sequence of SEQ ID NO: 6).

In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) an immunoglobulin heavy chain variable domain (V _H ) comprising the amino acid sequence set forth in SEQ ID NO: 8; b) an immunoglobulin light chain variable domain (V _L ) comprising the amino acid sequence set forth in SEQ ID NO: 10; c) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and an immunoglobulin V _L domain comprising the amino acid sequence set forth in SEQ ID NO: 10; d) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; e) an immunoglobulin V _L domain comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; f) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; g) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; Or h) an immunoglobulin comprising SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 seconds immunoglobulin V including the variable region _H shown by domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 hypervariable regions shown with V _L domain.

For ease of reference, the amino acid sequence of the hypervariable region of the secukinumab monoclonal antibody as determined by X-ray analysis using Chothia and colleagues' approach, based on Kabat definition, is provided in Table 1 below.

In a preferred embodiment, the constant region domain is also described, for example, in "Sequences of Proteins of Immunological Interest", Kabat EA et al, US Department of Health and Human Services, Public Health Service, National Institute of Health. Suitable human constant region domains. The DNA encoding V _L of secukinumab is shown in SEQ ID NO: 9. The DNA encoding V _H of Secukinumab is shown in SEQ ID NO: 7.

In some embodiments, the IL-17 antibody or antigen-binding fragment thereof (eg, secukinumab) comprises the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises 3 CDRs of SEQ ID NO: 10 and 3 CDRs of SEQ ID NO: 8. CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 can be found in Table 1 . The free cysteine (CysL97) in the light chain can be seen in SEQ ID NO: 6.

In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises 3 CDRs of SEQ ID NO: 14 and 3 CDRs of SEQ ID NO: 15. CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 can be found in Table 1 .

Hypervariable regions can be associated with any kind of framework region, but are preferably of human origin. Suitable framework regions are described in Kabat E.A et al., supra. Preferred heavy chain frameworks are those of human heavy chain frameworks, such as secukinumab antibodies. This may include, for example, FR1 (amino acids 1 to 30 of SEQ ID NO: 8), FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 (amino acids 67 to 98 of SEQ ID NO: 8) and FR4 ( Amino acids 117 to 127 of SEQ ID NO: 8). Taking into account the determined hypervariable regions of secukinumab by X-ray analysis, other preferred heavy chain frameworks are FR1-x (amino acids 1 to 25 of SEQ ID NO: 8), FR2-x (36 of SEQ ID NO: 8) in sequence. Amino acids #49), FR3-x (amino acids 61-95 of SEQ ID NO: 8) and FR4 (amino acids 119-127 of SEQ ID NO: 8). In a similar manner, the light chain framework comprises FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR2' (amino acids 36 to 50 of SEQ ID NO: 10), FR3' (58 to 80 of SEQ ID NO: 10) in the sequence. Amino acid 89) and FR4' (amino acids 99 to 109 of SEQ ID NO: 10).

In one embodiment, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) comprises at least a) a variable domain and constant region comprising the hypervariable regions CDR1, CDR2 and CDR3 of a human heavy chain in a sequence, or An immunoglobulin heavy chain or a fragment thereof comprising the fragments thereof (the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3); And b) an immunoglobulin light chain or fragment thereof comprising a variable domain and a constant portion or fragments thereof comprising the hypervariable regions CDR1', CDR2' and CDR3' of the human light chain in the sequence (the CDR1' is the amino acid sequence of SEQ ID NO:4) , Wherein the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6).

In one embodiment, the IL-17 antibody or antigen-binding fragment thereof a) a first domain comprising hypervariable regions CDR1, CDR2 and CDR3 in a sequence (the CDR1 has the amino acid sequence of SEQ ID NO: 1, wherein the CDR2 is Has the amino acid sequence of SEQ ID NO: 2, the CDR3 has the amino acid sequence of SEQ ID NO: 3); And b) a second domain comprising hypervariable regions CDR1', CDR2' and CDR3' in the sequence (the CDR1' has the amino acid sequence of SEQ ID NO: 4, and the CDR2' has the amino acid sequence of SEQ ID NO: 5, CDR3' has the amino acid sequence of SEQ ID NO: 6); And c) a peptide linker bound to the N-terminal end of the first domain and the C-terminal end of the second domain or the C-terminal end of the first domain and the N-terminal end of the second domain. It comprises a single-chain antibody or antigen-binding fragment thereof.

Alternatively, IL-17 antibodies or antigen-binding fragments thereof as used in the disclosed methods are derivatives of IL-17 antibodies (e.g., pegylated variants, glycosylation variants, affinity- presented by the sequences herein) Mature variants, etc.). For the V _H or V _L domain of the binding fragment is the same V _H or V _L domain in V _H or V _L domain substantially set out herein (e.g., - Alternatively, IL-17 antibody or an antigen for use in the disclosed method , As shown in SEQ ID NO: 8 and SEQ ID NO: 10). Human IL-17 antibodies disclosed herein may comprise a heavy chain substantially identical to that set forth in SEQ ID NO: 15 and/or a light chain substantially identical to that set forth in SEQ ID NO: 14. Human IL-17 antibodies disclosed herein may include a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibody disclosed herein comprises: a) a heavy chain comprising a variable domain and a constant portion of a human heavy chain having an amino acid sequence substantially identical to that set forth in SEQ ID NO: 8; And b) a human light chain, the light chain comprising a variable domain and a constant region having an amino acid sequence substantially identical to that set forth in SEQ ID NO: 10.

Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods can be an amino acid sequence variant of the reference IL-17 antibody provided herein (but containing CysL97). The invention also includes an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab), wherein one or more of the amino acid residues of the V _H or V _L domain of secukinumab (not CysL97) , Usually only slightly (eg 1 to 10), for example, by mutation, eg by site-directed mutagenesis of the corresponding DNA sequence. In all such cases of derivatives and variants, the IL-17 antibody or antigen-binding fragment thereof is about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more of the molecule. Preferably, the activity of human IL-17 at about 1 nM (= 30 ng/ml) at a concentration of about 1 nM or less can be inhibited to 50%, and the inhibitory activity is described in Example 1 of WO 2006/013107. It is measured in IL-6 production induced by hu-IL-17 in human dermal fibroblasts as described.

In some embodiments, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is a mature human IL comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 It binds to an epitope of -17. In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, an IL-17 antibody, e.g., secukinumab, binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains, the epitope being Leu74, Tyr85, His86 in one chain , Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains. The residue numbering scheme used to define this epitope is based on residues, one is the first amino acid of the mature protein (i.e., IL-17A, which lacks the 23 amino acid N-terminal signal peptide and starts with glycine). The sequence for immature IL-17A is shown in Swiss-Prot catalog Q16552. In some embodiments, the IL-17 antibody has a K _D of about 100-200 pM (eg, as determined by a Biacore® assay). In some embodiments, the IL-17 antibody has an IC ₅₀ of about 0.4 nM for in vitro neutralization of the biological activity of human IL-17A of about 0.67 nM. In some embodiments, the absolute bioavailability of IL-17 antibody administered subcutaneously (SC) ranges from about 60% to about 80%, such as about 76%. In some embodiments, the IL-17 antibody, such as secukinumab, has a elimination half-life of about 4 weeks (eg, about 23 days to about 35 days, about 23 days to about 30 days, such as about 30 days). . In some embodiments, the IL-17 antibody (eg, secukinumab) has a T _max of about 7-8 days.

A particularly preferred IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods is secukinumab as described in human antibodies, in particular Example 1 and Example 2 of WO 2006/013107. Other preferred IL-17 antibodies for use in the disclosed methods, kits and regimens are described in US Pat. Nos. 8,057,794; 8,003,099; 8,003,099; 8,110,191; 8,110,191; And 7,838,638 and US Published Patent Application Nos. 20120034656 and 20110027290, the entire contents of which are incorporated herein by reference.

Methods and uses of IL-17 antagonists for HS

Disclosed IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or IL-17 receptor binding molecule (e.g., IL The -17 receptor antibody or antigen-binding fragment thereof) can be used in vitro, ex vivo, or introduced into a pharmaceutical composition and administered in vivo to treat HS patients (eg, human patients).

HS is a chronic, inflammatory, scar disease with intermittent skin in the axilla, groin, genital anus and perineum of the body. This is also called translocation acne. Three diagnostic criteria establish HS diagnosis: conventional lesions (deep painful nodules [blind] boils in early primary lesions), or "tombstones" in abscesses, drainage, tangled scars, and secondary lesions )" open cotton fabric); Conventional topography (armpit, groin, genital, perineal and perianal zones, buttocks, and sub-mammary and inter-mammary sites; and chronic and recurrent (Margesson and Danby (2014) Best Practices and Res. Clin. Ob. And Gyn 28: 1013-1027).The body level of HS can be categorized using the Hurley clinical staging described in Table 2 below:

HS consists of clogging of the hair follicles, rupture of the tube and secondary inflammation. The patient initially experiences blockage in the follicular canal, which over time leads to tube leakage and horizontal rupture of the dermis. When the repair of folliculo-pilosebaceous (FPSB) fails, the hair follicle fragment stimulates three responses that initiate the HS disease process. The first is an inflammatory reaction triggered by the innate immune system, leading to purulent and tissue destruction and leading to foreign body reactions and extensive scarring. The second response leads to epithelialized sinus, which can evolve from stem cells derived from FPSB units that survive the destruction caused by the inflammatory response. Third, an invasive, proliferative gelatinous mass is produced in most cases consisting of a gel containing inflammatory cells, which are assumed to be precursors to the epithelialized urea described above. (See Margesson and Danby (2014)). As used herein, the phrase “slowing the progression of HS disease” means reducing the rate of development of any aspect of the HS disease process described above, particularly the inflammatory response. In some embodiments of the invention, treatment with an IL-17 antagonist (eg, secukinumab) slows HS disease progression.

HS relapse in patients includes papules, pustules or inflammatory nodules, pain and itching, abscesses, development of drainage, and any combination thereof. As used herein, “HS exacerbation” (and others) is defined as an increase of at least 25% with a minimal increase of AN of 2 relative to the abscesses and inflammatory nodule count (AN). In some embodiments of the invention, treatment according to the disclosed methods with an IL-17 antagonist (eg, secukinumab) prevents HS exacerbation and/or reduces the severity of HS exacerbation and/or exacerbates HS Reduces the frequency of In some embodiments, when the HS patient population is treated according to the disclosed methods, less than 5%, less than 10%, less than 15%, or less than 20% experience exacerbation during the first 16 weeks of treatment.

As used herein, the phrase “reducing the severity of HS exacerbations” and others reduces the intensity of HS exacerbations, such as reducing the number and/or size of abscesses and/or inflammatory nodules, specific Reducing the intensity of exacerbation components (e.g., reducing the number, size, thickness, etc. of abscesses and/or inflammatory nodules, reducing the degree of skin irritation (itching, pain), etc.), and/or It means reducing the duration of exacerbation (or its components).

As used herein, the phrase “reduction of the frequency of HS exacerbations” and others means reducing the incidence of HS exacerbations, eg, reducing the incidence of abscesses and/or inflammatory nodules. By reducing the frequency of HS exacerbations, patients will experience fewer HS relapses. The incidence of exacerbations can be assessed by monitoring patients over time to determine if the prevalence of exacerbations decreases.

As used herein, the phrase “prevention of HS exacerbation” means eliminating future HS exacerbation and/or exacerbation components.

The effectiveness of HS treatment can be assessed using a variety of known methods and tools for measuring HS disease status and/or HS clinical response. Some examples include Hurley's staging, Sartorius score, modified Sartorius score, HS physicians' global assessment (HS-PGA) score, visual analog scale (VAS) HS clinical response (HiSCR) based on the sum of scale or skin-related pain ratings (NRS: numeric rating scale), dermatology life quality index (DLQI), abscess and inflammatory nodules ), simplified HiSCR, EuroQuol-5D (EQ5D), hospital anxiety and depression scale, health care resource use, purulent psoriasis severity index (HSSI: Hidradenitis Suppurativa Severity Index), work productivity index (WPI), inflammation These include the inflamed body surface area (BSA), the Acne Inversa Severity Index (AISI), and the like. (See, e.g., Deckers and Prens (2016) Drugs 76:215-229; Sartorius et al. (2009) Br. J. Dermatol 161:831-39; Chiricozzi et al. (2015) Wounds 27(10): 258-264). In some embodiments, HS patients achieve HiSCR in response to HS treatment. In some embodiments, when the HS patient population is treated according to the disclosed methods, at least 41%, at least 50%, at least 51%, at least 61%, or at least 71% achieve HiSCR at 16 weeks of treatment.

Preferred scoring systems for the treatment response are HiSCR, simplified HiSCR, NRS (particularly NRS30), modified Sartorius score, HS-PGA, inflammatory lesion counts (number of abscesses, inflammatory nodules, and/or drainage fistulas), and DLQI .

The purulent psoriatic clinical response (HiSCR) is a measure of the clinical response to HS treatment. The HiSCR response to treatment (compared to baseline) is as follows: 1) at least 50% reduction in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of drainage fistulas. As used herein, “simplified HiSCR” or “sHiSCR” refers to a modified HiSCR that does not include the abscess number for the baseline (item 2 above) when evaluating lesion progression. In a preferred embodiment, HS patients achieve simplified HiSCR in response to HS treatment. In some embodiments, when the HS patient population is treated according to the disclosed methods, at least 41%, at least 50%, at least 51%, at least 61%, or at least 71% achieve simplified HiSCR at 16 weeks of treatment.

Pain can be assessed using a scored rating scale (NRS). In some embodiments, HS patients achieve improved NRS in response to HS treatment. NRS30 is defined as at least 30% pain reduction and at least 1 unit reduction from baseline in Patient's Global Assessment (PGA) of skin pain from baseline in patients with baseline score 3 or higher. In some embodiments, HS patients achieve NRS30 in response to HS treatment. In some embodiments, when the HS patient population is treated according to the disclosed methods, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS30 at 16 weeks of treatment.

DLQI is the best established skin quality of life tool. This consists of questions related to the impact of skin diseases on different aspects and feelings of daily life activities during the last week. Each question is scored from 0 (nothing at all) to 3 (very much). A total of 30 points is the maximum score, where 0 to 1 are ineffective in the patient's life, 2 to 5 are small effects, 6 to 10 are moderate effects, 11 to 20 are very large effects, and 21 to 30 are It is extremely effective. (See Finlay and Khan (1994) Clin Exp Dermatol 19:210-16). In some embodiments, HS patients achieve improved DLQI in response to HS treatment.

The Satorius HS score (also called HS score or HSS) is achieved by counting the areas of involvement, nodules and pus pockets in HS patients. (Sartorius et al. (2003) Br J Dermatol 149:211-13). Variant Sartorius HS scores include the original version of the HSS, which made small simplifications that make it more viable to use fewer specific lesions, for example, to include changes in the number of points given to each parameter in the score. It is a revision. (Sartorius et al. (2009) Br. J Dermatol. 161:831-839). In some embodiments, HS patients achieve improved modified Sartorius HS in response to HS treatment.

The HS Pseudo Comprehensive Assessment (HS-PGA) is a 6-scale evaluation scale (score ranging from 0 to 5) based on the number of HS lesions (ie abscesses, drainage fistulas, inflammatory nodules and non-inflammatory nodules). (Chiricozzi et al. (2015) Wounds 27(10):258-264). In some embodiments, HS patients achieved improved HS-PGA in response to HS treatment. In some embodiments, the HS patient achieves a clear, minimal or low HS-PGA score with at least a 2-grade improvement from baseline in response to HS treatment.

In some embodiments, the patient is treated for HS according to the method claimed for at least 36 weeks, at least 48 weeks, at least 52 weeks, or at least 2 years. In some embodiments, when the HS patient population is treated according to the disclosed methods, at least 30%, at least 40% of patients who responded to treatment at week 16 (e.g., patients who achieved HiSCR or simple HiSCR at week 16) , At least 50%, at least 60%, at least 70%, at least 80% or at least 90% continued response after 1 year of treatment (52 weeks). As used herein, the term “sustained” means that the result or goal (eg, pain reduction, inflammation reduction) is substantially maintained for a given time.

As used herein, the phrase “moderate to severe” refers to HS disease with five or more active inflammatory lesions (ie abscesses and/or inflammatory nodules) in which the patient affects at least two distinct anatomical sites. Refers to. In some embodiments, the HS patient has moderate to severe HS disease.

In some embodiments, the patient is diagnosed with HS for at least 1 year.

In some embodiments, the patient does not have extensive scarring as a result of HS (i.e., fistula less than 20, drained or non drained).

In some embodiments, the patient has had an inappropriate response to conventional systemic HS treatment in the past.

In some embodiments, the patient is an adolescent patient (12 years of age or older) with moderate to severe HS. In some embodiments, the patient is an adult patient with moderate to severe HS.

In some embodiments, in response to treatment according to the claimed method, the patient experiences rapid pain reduction as fast as one week after initial dosing as measured by VAS or NRS.

In some embodiments, the patient is a candidate for systemic treatment, i.e., HS disease is severe enough to require systemic intervention (e.g., greater than 5% BSA, Hurley II or stage II, etc.).

In some embodiments, the patient is an adult human patient with HS. In some embodiments, the patient is a pediatric human patient with HS. The upper age limit used to define pediatric patients varies among professionals and can include adolescents up to 21 years of age (e.g., Berhman RE, Kliegman R, Arvin AM, Nelson WE.Nelson Textbook of Pediatrics). , 15th Ed.Philadelphia: WB Saunders Company; 1996; 2.Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed.New York: McGraw-Hill; 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams &Wilkins; 1994). As used herein, the term “child” generally refers to humans who are 16 years of age or older, which is the definition of pediatric humans as used by the US FDA. However, other examples of pediatric patients include patients older than 14 and 12 years of age.

In some embodiments, the pediatric patient has an IL-17 antibody (e.g., weekly for week 0, week 1, week 2, week 3, and week 4, followed by week 2) at a dose of about 300 mg regardless of the patient's body weight. For example, SC dose of secukinumab) is administered.

In some embodiments, the pediatric patient has a dose of about 300 mg irrespective of the patient's body weight for week 0, week 1, week 2, week 3 and week 4, followed by week 4 (monthly) IL-17 The SC dose of the antibody (eg, secukinumab) is administered.

In some embodiments, the pediatric patient has a dose of about 75 mg if the patient's weight is less than 25 kg or 150 mg if the patient's weight is greater than 25 kg every week for 0 weeks, 1 week, 2 weeks, 3 weeks and 4 weeks, The SC dose of the IL-17 antibody (eg, secukinumab) is then administered every 2 or 4 weeks thereafter. In some embodiments, the pediatric patient has a dose of about 75 mg if the patient's weight is less than 50 kg or 150 mg if the patient's weight is greater than 50 kg every week for 0 weeks, 1 week, 2 weeks, 3 weeks and 4 weeks, The SC dose of the IL-17 antibody (eg, secukinumab) is then administered every 2 or 4 weeks thereafter.

In some embodiments, the pediatric patient has a dose of about 150 mg if the patient's weight is less than 25 kg or 300 mg if the patient's weight is greater than 25 kg every week for 0 weeks, 1 week, 2 weeks, 3 weeks and 4 weeks, The SC dose of the IL-17 antibody (eg, secukinumab) is then administered every 2 or 4 weeks thereafter. In some embodiments, the pediatric patient has a dose of about 150 mg if the patient's weight is less than 50 kg or 300 mg if the patient's weight is greater than 50 kg, weekly for 0 weeks, 1 week, 2 weeks, 3 weeks and 4 weeks, The SC dose of the IL-17 antibody (eg, secukinumab) is then administered every 2 or 4 weeks thereafter.

In some embodiments, in response to treatment according to the claimed method, the patient experiences rapid CRP reduction as fast as 1 week after initial dosing as measured by a standard CRP assay or a high sensitivity CRP (hsCRP) assay. As used herein, “C-reactive protein” and “CRP” refer to serum C-reactive protein, a plasma protein commonly used as an indicator of an acute phase response to inflammation. CRP levels in plasma can be given at any concentration, such as mg/dl, nmol/L. CRP levels can be measured by a variety of standard assays, such as radioimmunoassay, electroimmunometry, immunoturbidity, ELISA, turbidity, fluorescence polarization immunoassay and laser turbidity. The test for CRP may use a standard CRP test or a high-sensitivity CRP (hs-CRP) test (ie, a high-sensitivity test capable of measuring low-level CRP in a sample using a laser turbidity method). Kits for detecting CRP levels can be purchased from various companies, such as Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc. have.

IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or IL-17 receptor binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof) can be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such compositions may contain carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art, in addition to IL-17 antagonists. The characteristics of the carrier will depend on the route of administration. Pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for the treatment of certain targeted disorders. For example, the pharmaceutical composition may also include an anti-inflammatory agent. These additional factors and/or agents are used to produce a synergistic effect by an IL-17 binding molecule, or an IL-17 antagonist, such as an IL-17 binding molecule (eg, an IL-17 antibody or antigen-binding thereof) Fragments, eg secukinumab) or IL-17 receptor binding molecules (eg, IL-17 antibodies or antigen-binding fragments thereof) can be included in the pharmaceutical composition to minimize side effects. In a preferred embodiment, the pharmaceutical composition for use in the disclosed method comprises 150 mg/ml of secukinumab.

Pharmaceutical compositions for use in the disclosed methods can be prepared in a conventional manner. In one embodiment, the pharmaceutical composition is provided in lyophilized form. For immediate administration, it is dissolved in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. If it is desirable to construct larger volumes of solution for administration by drop injection than bolus injection, it may be advantageous to introduce human serum albumin or the patient's own heparinized blood into saline during formulation. The presence of an excess of this physiologically inactive protein prevents the antibody from adsorbing and disappearing on the walls of the piping and vessels used with the drip solution. When albumin is used, a suitable concentration is 0.5% to 4.5% by weight of the saline solution. Other formulations include liquid formulations ready for use.

Antibodies, for example, antibodies to IL-17 are typically formulated as ready-to-use aqueous forms for parenteral administration or as a lyophilisate for reconstitution with a suitable diluent prior to administration. In a preferred embodiment of the disclosed methods and uses, an IL-17 antagonist, such as an IL-17 antibody, eg secukinumab, is formulated into a ready-to-use (ie, stable-use preparation) liquid pharmaceutical formulation. In some embodiments of the disclosed methods and uses, an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, is formulated as a lyophilisate. Suitable lyophilisate formulations can be reconstituted into small liquid volumes (e.g., 2 mL or less, e.g. 2 mL, 1 mL, etc.) to allow subcutaneous administration, and can provide low levels of antibody aggregation to the solution. have. The use of antibodies as active ingredients in pharmaceuticals, including the products HERCEPTIN™ (trastuzumab), RITUXAN™ (rituximab), SYNAGIS™ (palivizumab) and the like, is now widespread. Techniques for the purification of antibodies to pharmaceutical grades are known in the art. A therapeutically effective amount of an IL-17 antagonist, eg, an IL-17 binding molecule (eg, an IL-17 antibody or antigen-binding fragment thereof, eg secukinumab) or an IL-17 receptor binding molecule (eg For example, when an IL-17 antibody or antigen-binding fragment thereof) is administered by intravenous, intradermal or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free parenterally acceptable solution. Pharmaceutical compositions for intravenous, intradermal or subcutaneous injection may contain isotonic vehicles in addition to IL-17 antagonists, such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, Lactic Acid Ringer's solution, or other vehicles known in the art. .

In practicing some of the therapeutic methods or uses of the invention, a therapeutically effective amount of an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. For example, secukinumab) or IL-17 receptor binding molecule (eg, IL-17 antibody or antigen-binding fragment thereof) is administered to a patient, eg, a mammal (eg, human). It is understood that the disclosed methods use IL-17 antagonists (e.g., secukinumab) to provide treatment for HS patients, but if the patient is ultimately treated with an IL-17 antagonist, then such IL-17 antagonist treatment must be single It does not rule out that it is a therapy. Indeed, if a patient is selected for treatment with an IL-17 antagonist, the IL-17 antagonist (e.g., secukinumab) alone or in combination with other agents and therapeutics to treat HS patients, e.g., at least It can be administered according to the methods of the invention in combination with one additional HS agent. When co-administered with one or more additional HS agent(s), the IL-17 antagonist can be administered simultaneously or sequentially with other agents. When administered sequentially, the attending physician will determine the appropriate sequence for administration of the IL-17 antagonist in combination with other agents and the appropriate dosage for co-delivery.

Various therapeutic agents may advantageously be combined with an IL-17 antibody disclosed during the treatment of HS, such as secukinumab. These conventional therapies include topical treatment (cream [nonsteroidal or steroidal], washing solution, disinfectant), systemic treatment (eg, by biologics, antibiotics, hormones, retinoids or chemical aggregates), disinfectants, photodynamic therapy And surgical intervention (laser, drainage or incision, resection). Additional combination treatments include the use of JAK inhibitors, IL-23 targeted treatment (eg, guselcumab), microbiome treatment, and sclerotherapy.

Non-limiting examples of topical HS agents for use with the disclosed IL-17 antibodies, such as secukinumab, are benzoyl peroxide, topical steroid creams, topical antibiotics in the aminoglycoside group, such as clindamycin, gentamicin and erythromycin , Resorcinol cream, iodine scrub and chlorhexidine.

Non-limiting examples of HS agents used in systemic treatment for use with the disclosed IL-17 antibodies, such as secukinumab, are additional IL-17 antagonists (Execizumab, Brodalumab, CJM112), tumor necrosis factor-alpha (TNF-alpha) blockers (e.g. Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) and Simponi® (golimumab)), interleukin 12/23 blockers (e.g. Stelara® (Ustekinumab), Tasocitinib and Briakinumab), p19 inhibitors, PDE4 inhibitors, Leukotriene A4 hydrolase inhibitors, complement pathway inhibitors, C5a inhibitors, IL-1 antagonists (Kanakinumab, Liloncept) , Anakinra), CXCR1/2 inhibitors, IL-18 antagonists, IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, B-cell depleting agents (especially CD20 antagonists, and BAFF-R and CD40 antagonists), IL-21 antagonists, IL-22 antagonists, VEGF antagonists, CXCL antagonists, MMP antagonists and defensin antagonists (eg, receptor decoy, antagonistic antibodies, etc.).

Additional HS formulations for use in combination with an IL-17 antibody disclosed during the treatment of HS, such as secukinumab, are retinoids such as acitretin (e.g. Soriatane®) and isotretinoin, immune system inhibitors (e.g. rapamycin, T-cell blockers (e.g. Amevive® (Alepasept) and Raptiva® [Epalizumab]) cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, leflunomide, tacrolimus, etc.), Hydroxyurea (e.g. Hydrea®), sulfasalazine, 6-thioguanine, fumarate (e.g. dimethylfumarate and fumaric acid esters), azathioprine, colchicine, alitretinoin, steroids, corticosteroids, sertoli Zumab, apremilast, mometasone, rosiglitazone, pioglitazone, botulinum toxin, triamcinolone, IFX-1 (InflaRx), bimekizumab (UCB), MaBp1 (XBiotech), LY-3041658 (Eli Lilly), TE-2232 (Immunwork), NSAIDs, prescription drugs, ketoprofen, codeine, gabapentin, pregabalin gentanyl, antibiotics (topical, oral, IV) (e.g., separate or in combination, clindamycin, rifampin, tetracycline, sare Cycline, doxycycline, minocycline, limcycline, trimetoprim-sulfametoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole), corticosteroids (injectable or oral), anti-androgen/hormone drugs (oral contraceptives) , Spironolactone, Finasteride, Dutasteride, Progesterone IUD, Ciproterone Acetate, Ethyniloestradiol, Gestoden, Norgestimate, Desogestrel, Drospyrenone, Spironolactone), Triamcinolone, Aceto Need, MEDI8968, hydroxychloroquine, dapsone, metformin, adapalene, azelaic acid and zinc.

Preferred combinations for use in the disclosed kits, methods and uses are IL-17 binding molecules (e.g., in combination with TNF alpha inhibitors (e.g. adalimumab) or IL-1β blockers (e.g. canakinumab)) For example, IL-17 antibody or antigen-binding fragment thereof, eg secukinumab) or IL-17 receptor binding molecule (eg, IL-17 receptor antibody or antigen-binding fragment thereof).

Those skilled in the art will be able to know the appropriate dosage of the HS preparation for co-delivery with the disclosed IL-17 antibodies, such as secukinumab.

IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or IL-17 receptor binding molecule (e.g., IL- The 17 receptor antibody or antigen-binding fragment thereof) is conveniently administered parenterally, for example intravenously (eg, with the anterior pole or other peripheral vein), intramuscularly or subcutaneously. The duration of intravenous (IV) treatment with the pharmaceutical compositions of the present invention will depend on the severity of the disease and condition being treated and the individual response of each individual patient. Subcutaneous (SC) treatment with the pharmaceutical compositions of the present invention is also contemplated. The healthcare provider will determine the appropriate duration of IV or SC treatment with the pharmaceutical composition of the present invention and when to administer the therapeutic agent. In a preferred embodiment, the IL-17 antagonist (eg, secukinumab) is administered via the subcutaneous (SC) route.

IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or IL-17 receptor binding molecule (e.g., IL- 17 receptor antibody or antigen-binding fragment thereof) can be administered intravenously (IV) to a patient at biweekly, e.g., about 10 mg/kg every other week for 0 weeks, 2 weeks and 4 weeks, and then starting for 6 weeks Every two weeks, for example, about 300 mg to about 450 mg (eg, about 300 mg, about 450 mg) can be administered subcutaneously (SC) to the patient. In this way, the patient can be dosed with about 10 mg/kg IV for 0 weeks, 2 weeks, 4 weeks, and then the patient is about 300 mg for 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, etc. To about 450 mg (eg, about 300 mg, about 450 mg) of IL-17 antagonist (eg, secukinumab) is administered SC.

Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, the IL-17 receptor antibody or antigen-binding fragment thereof) can be administered intravenously (IV) to a patient at about 10 mg/kg every other week for 0, 2, and 4 weeks, followed by 8 It may be administered subcutaneously (SC) to the patient starting at weekly, for example, about 300 mg to about 450 mg (eg, about 300 mg, about 450 mg) monthly (every 4 weeks). In this way, the patient can be dosed at about 10 mg/kg IV for 0 weeks, 2 weeks, 4 weeks, after which the patient is from about 300 mg to about 450 for 8 weeks, 12 weeks, 16 weeks, 20 weeks, etc. mg (eg, about 300 mg, about 450 mg) of IL-17 antagonist (eg, secukinumab) is administered SC.

Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, the IL-17 receptor antibody or antigen-binding fragment thereof) may be, for example, about 300 mg to about 450 mg per week for weeks 0, 1, 2, and 3 (e.g., about 300 mg, about 450) mg) to the patient, followed by SC administration to the patient, e.g., from about 300 mg to about 450 mg (e.g., about 300 mg, about 450 mg) every 2 weeks starting for 4 weeks. Can. In this way, the patient is about 300 mg to about 450 mg (e.g., about 300 mg, for 0 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.) About 450 mg) of IL-17 antagonist (eg, secukinumab) is administered SC.

Preferably, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g. For example, the IL-17 receptor antibody or antigen-binding fragment thereof) may be, for example, about 300 mg to about 450 mg per week for weeks 0, 1, 2, and 3 (e.g., about 300 mg, about 450) mg) can be administered to the patient as SC, and then administered to the patient every month (every 4 weeks), e.g., from about 300 mg to about 450 mg (e.g., about 300 mg, about 450 mg), starting for 4 weeks. SC can be administered. In this way, the patient is about 300 mg to about 450 mg (e.g., about 300 mg, for 0 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, etc.) About 450 mg) of IL-17 antagonist (eg, secukinumab) is administered SC.

Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, IL-17 receptor antibody or antigen-binding fragment thereof) is the lowest of more than 30 mcg/mL, more than 40 mgc/mL, more than 60 mcg/mL, more than 80 mcg/mL, or more than 100 mcg/mL during maintenance regimen SC may be administered to the patient in a dose sufficient to provide a concentration.

More preferably, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, an IL-17 receptor antibody or antigen-binding fragment thereof) can be administered to a patient without a loading regime, e.g., an antagonist from about 300 mg to about 450 mg every 2 weeks (e.g., about 300 mg, About 450 mg) to the patient. In this way, the patient has about 300 mg to about 450 mg (e.g., about 300 mg, about 450 mg) of IL-17 antagonist for 0 weeks, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, etc. (E.g., secukinumab) is administered SC.

Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, an IL-17 receptor antibody or antigen-binding fragment thereof) can be administered to a patient without a loading regime, e.g., an antagonist from about 300 mg to about 450 mg every 4 weeks (e.g., about 300 mg, about 450 mg) to the patient. In this way, the patient has about 300 mg to about 450 mg (e.g., about 300 mg, about 450 mg) of IL-17 antagonist for 0 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, etc. (E.g., secukinumab) is administered SC.

Alternatively, IL-17 antagonists, e.g. IL-17 antibodies, e.g. secukinumab, can be topically and orally (e.g., Rani Therapeutics technology, e.g. 8,734,429; 9,492,378; 9,456,988; 9,415,004; 9,629,799; 9,757,548; 9,757,514; 9,402,806; US Published Applications 2017/0189659, 2017/0100459 By intestinal lumen).

At 12, 16, 20, 24, 48, or 52 weeks of treatment (e.g., any HS scoring system disclosed herein, e.g. HiSCR, simplified HiSCR, NRS [particularly NRS30], modified sar IL-17 antagonist, e.g. IL-17 binding molecule (e.g. as measured by Torius score, HS-PGA, number of inflammatory lesions (number of abscesses, inflammatory nodules, and/or drainage fistulas), DLQI, etc.) , Inappropriate response to treatment with an IL-17 antibody or antigen-binding fragment thereof, eg secukinumab) or an IL-17 receptor binding molecule (eg, IL-17 receptor antibody or antigen-binding fragment thereof) It will be appreciated that dose escalation may be required for certain patients, such as HS patients with. Thus, the SC dosage of secukinumab is greater than about 300 mg to about 450 mg SC, for example about 350 mg, about 400 mg, about 450 mg (for the original 300 mg dose); About 500 mg, about 550 mg, about 600 mg (for the original 450 mg dose), and the like; Similarly, the IV dose is greater than about 10 mg/kg, e.g., about 11 mg/kg, 12 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/ kg. Dosage reduction also occurs in certain patients, such as HS patients, who have side effects or adverse reactions to treatment with an IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab). It will also be understood that it may be necessary. Thus, the dosage of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) is less than about 300 mg to about 450 mg SC, e.g., about 250 mg, about 200 mg, about 150 mg (for the original 300 mg dose); About 400 mg, about 350 mg, about 300 mg (for the original 450 mg dose), and the like. Similarly, IV dosages are less than about 10 mg/kg, e.g., about 9 mg/kg, 8 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/ kg. In some embodiments, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g. secukinumab) or an IL-17 receptor binding molecule (e.g. For example, an IL-17 receptor antibody or antigen-binding fragment thereof) can be administered to a patient at an initial dose delivered with an SC delivered of 300 mg or 450 mg, and the dose thereafter is about 450 mg as required by a physician. (In the case of the original 300 mg dose) or about 600 mg (in the case of the original 450 mg dose).

As used herein, “fixed dose” refers to an even dose, that is, a dose that does not change regardless of the patient's characteristics. Thus, fixed doses differ from variable doses, such as body surface area based doses or body weight based doses (typically given in mg/kg). In preferred embodiments of the disclosed methods, uses, pharmaceutical compositions, kits, etc., fixed doses of IL-17 antibodies to HS patients, e.g., fixed doses of secukinumab, e.g., from about 75 mg to about 450 mg, fixed Dosage of secukinumab, eg, about 75 mg, about 150 mg, about 300 mg, about 400 mg, or about 450 mg of secukinumab is administered.

The timing of dosing is generally measured from the date of the first dose of secukinumab (also known as the “baseline”). However, health care providers usually use different naming conventions to identify dosing schedules as described in Table 3 .

In particular, week 0 may be referred to as one week by some health care providers, while day 0 may be referred to as day 1 by some health care providers. Thus, other physicians may assign doses, for example, given for 3 weeks / 21 days, 3 weeks / 22 days, 4 weeks / 21 days, 4 weeks / 22 days, but this is the same dosing schedule It may be to refer to. For consistency, the first dosing week will be referred to herein as week 0, while the first dosing day will be referred to as day 1. However, this nomenclature convention is simply used for consistency and should not be construed as a limitation, that is, the weekly dosing of IL-17 antibodies irrespective of whether the physician refers to a particular week as "week 1" or "week 2". It will be understood by those skilled in the art as providing weekly doses.

In one dosing regimen, the antibody is administered for 0 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, etc. Some providers may refer to this regimen weekly for 5 weeks, followed by 8 weeks and then monthly (or every 4 weeks), while other providers may refer to this regimen every 4 weeks for weeks, then for 4 weeks You can start and refer to it every month (or every 4 weeks) thereafter. Patients are given injections at week 0, week 1, week 2, and week 3, followed by weekly dosing once a month starting at week 1) Patients at week 0, week 1, week 2, week 3, and week 4 Administering the injection, then starting once at week 8 and dosing once a month; 2) Patients are administered injections at week 0, week 1, week 2, week 3 and week 4, followed by dosing every 4 weeks; And 3) Patients will be understood by those skilled in the art to administer injections at week 0, week 1, week 2, week 3, and week 4, followed by monthly dosing.

In one dosing regimen, the antibody is administered for 0 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc. Some providers may refer to this regimen weekly for 5 weeks, followed by 6 weeks, and then every other week (or every 2 weeks), while others may refer to this regimen every 4 weeks, then 4 weeks It can be referred to as every other week (or every two weeks) starting thereafter. Patients are given injections at week 0, week 1, week 2 and week 3 followed by weekly (or every week) dosing every other week 1) Weeks 0, week 1, week 2, week 3 Administering injections at weeks and 4 weeks, followed by dosing every other week (or every 2 weeks) starting at week 6; 2) administering injections to patients at week 0, week 1, week 2, week 3 and week 4, followed by dosing every 2 weeks; And 3) Patients will be understood by those skilled in the art to administer injections at week 0, week 1, week 2, week 3, and week 4, followed by every other week.

As used herein, the phrase “formulated in a dosage amount that allows [the route of administration] of the [designated dose] to be delivered” means that a given pharmaceutical composition is desired through the designated route of administration (eg, SC or IV). It is used to mean that it can be used to provide a dose of an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab. As an example, if the desired SC dose is 300 mg, the clinician will have a 2 ml IL-17 antibody formulation with a concentration of 150 mg/ml, a 1 ml IL-17 antibody formulation with a concentration of 300 mg/ml, and a concentration of 600 mg. 0.5 ml of IL-17 antibody formulation, etc., can be used. In each of these cases, this IL-17 antibody formulation is at a concentration high enough to allow subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery typically requires delivery of a volume of about 2 ml or less, preferably about 1 ml or less. Preferred formulations are about 25 mg/mL to about 150 mg/ml of secukinumab, about 10 mM to about 30 mM histidine pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 It is a ready-to-use liquid pharmaceutical composition comprising mM to about 20 mM methionine.

As used herein, the phrase “a container with a sufficient amount of an IL-17 antagonist that allows delivery of a [designated dose]” can be used to provide the desired dose (eg, as part of a pharmaceutical composition. ) Is used to mean that the volume of IL-17 antagonist is placed inside a given container (eg, vial, pen, syringe). As an example, if the desired dose is 300 mg, the clinician will contain 2 ml from a container containing the IL-17 antibody formulation at a concentration of 150 mg/ml, and a container containing the IL-17 antibody formulation at a concentration of 300 mg/ml. 1 ml from, 0.5 ml from a container containing an IL-17 antibody formulation with a concentration of 600 mg/ml, and the like can be used. In each of these cases, this container has an amount of IL-17 antagonist sufficient to allow delivery of the desired 300 mg dose.

In some embodiments of the disclosed uses, methods, and kits, the dose of an IL-17 antibody (eg, secukinumab) or antigen-binding fragment thereof is about 300 mg, or an IL-17 antibody (eg, three Cookienumab) or an antigen-binding fragment thereof is included in the liquid pharmaceutical formulation at a concentration of 150 mg/ml, and 2 ml of the pharmaceutical formulation are two pre-filled syringes, injection pens or each with 1 ml of the pharmaceutical formulation. It is placed in the auto injector. In this case, the patient receives 2 injections of 1 ml each for a total dose of 300 mg during each administration. In some embodiments, the dose of the IL-17 antibody (eg, secukinumab) or antigen-binding fragment thereof is about 300 mg, and the IL-17 antibody (eg, secukinumab) or antigen-binding thereof Fragments are included in the liquid pharmaceutical formulation at a concentration of 150 mg/ml, and 2 ml of the pharmaceutical formulation is placed in an autoinjector or PFS. In this case, the patient receives one injection of 2 ml for a total dose of 300 mg during each administration. In a method using 2 ml of one injection (i.e., via a single PFS or autoinjector) (i.e., a "single-dose formulation"), drug exposure (AUC) and maximum concentration (C _max ) are For example, it is equivalent to using 2 injections of 1 ml (i.e., "multi-dose formulation") via 2 PFS or 2 AI (i.e., within the range of allowable fluctuations according to US FDA standards). ).

As a method of treating purulent cholineitis (HS), IL-17 antibody at a dose of about 300 mg to about 450 mg per week for 0 weeks, 1 week, 2 weeks, and 3 weeks for patients in need of treatment (E.g., secukinumab) or an antigen-binding fragment thereof administered subcutaneously (SC), followed by a) starting for 4 weeks, monthly (every 4 weeks); Or b) Disclosed herein is a method comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks. IL-17 antibody or antigen-binding fragment thereof administered subcutaneously (SC) at a dose of about 300 mg to about 450 mg per week for 0, 1, 2, and 3 weeks to patients in need of treatment of HS And then a) every 4 months starting every 4 weeks (every 4 weeks); Or b) an IL-17 antibody for use in treating HS (e.g., secuki) comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks Noumab) or antigen-binding fragments thereof are also disclosed herein. Alternatively, patients in need of treatment with HS may receive IL-17 antibody or antigen-binding fragment thereof subcutaneously at a dose of about 300 mg to about 450 mg per week for week 0, week 1, week 2 and week 3 (SC) dosing, followed by a) monthly for 4 weeks (every 4 weeks); Or b) IL-17 antibody for use in the manufacture of a medicament for treating HS, including administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks (e.g. E.g. secukinumab) or antigen-binding fragments thereof are disclosed herein.

As a method of treating purulent cholineitis (HS), IL-17 antibody at a dose of about 300 mg to about 450 mg per week for 0 weeks, 1 week, 2 weeks, and 3 weeks for patients in need of treatment (E.g., secukinumab) or an antigen-binding fragment thereof administered subcutaneously (SC), followed by a) starting for 4 weeks, monthly (every 4 weeks); Or b) a method disclosed herein comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks, wherein the IL-17 antibody or antigen-binding fragment thereof Binds to the epitope of the IL-17 homodimer with two mature IL-17 protein chains, the epitope being Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 And Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, the IL-17 antibody has a K _D of about 100-200 pM as measured by a biosensor system (e.g., BIACORE), IL-17 antibodies have an in vivo half-life of about 23 to about 30 days. IL-17 antibody or antigen-binding fragment thereof administered subcutaneously (SC) at a dose of about 300 mg to about 450 mg per week for 0, 1, 2, and 3 weeks to patients in need of treatment of HS And then a) every 4 months starting every 4 weeks (every 4 weeks); Or b) an IL-17 antibody for use in treating HS (e.g., secuki) comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks Numab) or an antigen-binding fragment thereof is also disclosed herein, wherein the IL-17 antibody or antigen-binding fragment thereof binds to the epitope of the IL-17 homodimer having two mature IL-17 protein chains, and the epitope Contains Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in another chain, IL-17 antibody Is a K _D of about 100 to 200 pM as measured by a biosensor system (eg, BIACORE®), and the IL-17 antibody has an in vivo half-life of about 23 to about 30 days. Alternatively, patients in need of treatment with HS may receive IL-17 antibody or antigen-binding fragment thereof subcutaneously at a dose of about 300 mg to about 450 mg per week for week 0, week 1, week 2 and week 3 (SC) administration, followed by a) monthly for 4 weeks (every 4 weeks); Or b) IL-17 antibody for use in the manufacture of a medicament for treating HS, including administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks (e.g. E.g. secukinumab) or antigen-binding fragments thereof are disclosed herein, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of the IL-17 homodimer having two mature IL-17 protein chains , The epitope comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in another chain, IL The -17 antibody has a K _D of about 100-200 pM as measured by a biosensor system (eg BIACORE), and the IL-17 antibody has an in vivo half-life of about 23 days to about 30 days.

As a method of treating purulent cholineitis (HS), IL-17 antibody at a dose of about 300 mg to about 450 mg per week for 0 weeks, 1 week, 2 weeks, and 3 weeks for patients in need of treatment (E.g., secukinumab) or an antigen-binding fragment thereof administered subcutaneously (SC), followed by a) starting for 4 weeks, monthly (every 4 weeks); Or b) a method disclosed herein comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks, wherein the IL-17 antibody or antigen-binding fragment thereof I) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and an immunoglobulin V _L domain comprising the amino acid sequence set forth in SEQ ID NO: 10; ii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; Or iii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 _L domain. IL-17 antibody or antigen-binding fragment thereof administered subcutaneously (SC) at a dose of about 300 mg to about 450 mg per week for 0, 1, 2, and 3 weeks to patients in need of treatment of HS And then a) every 4 months starting every 4 weeks (every 4 weeks); Or b) an IL-17 antibody for use in treating HS (e.g., secuki) comprising administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks Numab) or an antigen-binding fragment thereof is also disclosed herein, wherein the IL-17 antibody or antigen-binding fragment thereof is i) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and set forth in SEQ ID NO: 10 An immunoglobulin V _L domain comprising an amino acid sequence; ii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; Or iii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 _L domain. Alternatively, patients in need of treatment with HS may receive IL-17 antibody or antigen-binding fragment thereof subcutaneously at a dose of about 300 mg to about 450 mg per week for week 0, week 1, week 2 and week 3 (SC) dosing, followed by a) monthly for 4 weeks (every 4 weeks); Or b) IL-17 antibody for use in the manufacture of a medicament for treating HS, including administering SC at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks (e.g. E.g. secukinumab) or an antigen-binding fragment thereof disclosed herein, wherein the IL-17 antibody or antigen-binding fragment thereof i) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and SEQ ID NO: An immunoglobulin V _L domain comprising the amino acid sequence set forth as 10; ii) an immunoglobulin V _H domain comprising the hypervariable region set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable region set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; Or iii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 _L domain.

In preferred embodiments of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg or about 450 mg.

In a preferred embodiment of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment thereof is SC administered at a dose of about 300 mg every week for 0 weeks, 1 week, 2 weeks and 3 weeks, followed by 4 SC is administered at a dose of about 300 mg every other week (every two weeks) starting during the week.

In another preferred embodiment of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment thereof is SC administered at a dose of about 300 mg per week for 0 weeks, 1 week, 2 weeks and 3 weeks, after which SC is administered at a dose of about 300 mg per month (every 4 weeks) starting at 4 weeks.

In a preferred embodiment of the disclosed methods, uses, and kits, the patient has a (simplified) purulent pneumonitis clinical response (HiSCR), scored rating scale (NRS), modified Sartorius HS score, purulent pneumonitis-pseudo comprehensive evaluation ( HS-PGA), or skin quality of life index (DLQI), achieves a sustained response after 1 year of treatment.

In preferred embodiments of the disclosed methods, uses, and kits, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient has been treated with systemic agents for HS in the past. In preferred embodiments of the disclosed methods, uses and kits, the systemic agent is selected from the group consisting of topical treatment, antibiotics, immune system inhibitors, TNF-alpha inhibitors, IL-1 antagonists, and combinations thereof.

In some embodiments of the disclosed methods, uses and kits, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient has not been treated with systemic or topical treatment for HS in the past.

In a preferred embodiment of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment is administered in combination with at least one of a TNF-alpha inhibitor, antibiotic, IL-1 inhibitor or immunosuppressant.

In a preferred embodiment of the disclosed methods, uses and kits, the dose of IL-17 antibody or antigen-binding fragment is about 300 mg. In another preferred embodiment of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 450 mg.

In preferred embodiments of the disclosed methods, uses and kits, the patient has moderate to severe HS.

In preferred embodiments of the disclosed methods, uses and kits, the patient is an adult. In some embodiments of the disclosed methods, uses, and kits, the patient is adolescent.

In preferred embodiments of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment is placed in a pharmaceutical formulation, the pharmaceutical formulation further comprising a buffer and a stabilizer. In some embodiments of the disclosed methods, uses and kits, the pharmaceutical formulation is in liquid form. In some embodiments of the disclosed methods, uses, and kits, the pharmaceutical formulation is in lyophilized form. In some embodiments of the disclosed methods, uses and kits, the pharmaceutical formulation is placed in a pre-filled syringe, vial, injection pen or autoinjector.

In a preferred embodiment of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg, and the pharmaceutical formulation is in a means of administration selected from the group consisting of pre-filled syringes, injection pens and auto-injectors. Placed, the means is placed in a kit, the kit further includes instructions for use.

In a preferred embodiment of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg, the pharmaceutical formulation is placed in an autoinjector or prefield syringe, and the autoinjector or prefield syringe is It is placed in a kit, and the kit further includes instructions for use.

In a preferred embodiment of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg, the pharmaceutical formulation is placed in an autoinjector or prefield syringe, and the autoinjector or prefield syringe is It is placed in a kit, and the kit further includes instructions for use.

In a preferred embodiment of the disclosed methods, uses and kits, the dose of the IL-17 antibody or antigen-binding fragment is about 450 mg, the pharmaceutical formulation is placed in an autoinjector or prefield syringe, and the autoinjector or prefield syringe is It is placed in a kit, and the kit further includes instructions for use.

In a preferred embodiment of the disclosed methods, uses and kits, the dose is 300 mg, which is administered as a single subcutaneous administration in a total volume of 2 ml from a formulation comprising 150 mg/ml of an IL-17 antibody or antigen-binding fragment. , The patient's pharmacological exposure to an IL-17 antibody or antigen-binding fragment is that of a patient to an IL-17 antibody or antigen-binding fragment using two separate subcutaneous doses of a total volume of 1 ml each of the same formulation. Equivalent to pharmacological exposure.

In a preferred embodiment of the disclosed methods, uses and kits, the dose is 300 mg, which is administered in two separate subcutaneous volumes of 1 ml each from a formulation comprising 150 mg/ml of the IL-17 antibody or antigen-binding fragment. Is administered as.

In preferred embodiments of the disclosed methods, uses and kits, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient has an HS-PGA score of 3 or higher. In some embodiments, the patient is selected for treatment based on an HS-PGA score of 3 or higher.

In preferred embodiments of the disclosed methods, uses and kits, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient is classified as Hurley II or III stage. In some embodiments, the patient is selected for treatment based on the classification of the Hurley II or III stage.

In a preferred embodiment of the disclosed methods, uses and kits, the patient achieves (simplified) HiSCR at 16 weeks of treatment.

In a preferred embodiment of the disclosed methods, uses and kits, the patient achieves NRS30 at 16 weeks of treatment.

In a preferred embodiment of the disclosed method, use and kit, the patient has reduced HS exacerbation at 16 weeks of treatment.

In a preferred embodiment of the disclosed methods, uses and kits, the patient achieves a reduction of 6 or less as measured by DLQI at 16 weeks of treatment.

In a preferred embodiment, when the disclosed method, use or kit is used to treat a population of patients with moderate to severe HS, at least 51% of the patients achieve a simplified HiSCR at 16 weeks of treatment in response to the administration step. .

In a preferred embodiment, when the disclosed methods, uses or kits are used to treat a population of patients with moderate to severe HS, at least 40% of the patients achieve an NRS30 response at 16 weeks of treatment in response to the administration step.

In a preferred embodiment, when the disclosed method, use or kit is used to treat a population of patients with moderate to severe HS, less than 15% of the patients experience HS exacerbation for 16 weeks of treatment in response to the administration step.

In preferred embodiments of the disclosed methods, uses, and kits, prior to treatment with an IL-17 antibody or antigen-binding fragment thereof, the patient does not have extensive scarring as a result of HS (fistula less than 20). In some embodiments, the patient is selected for treatment based on not having extensive scarring as a result of HS (fistula less than 20).

In preferred embodiments of the disclosed methods, uses and kits, the patient is further treated with at least one topical agent and at least one disinfectant in combination with an IL-17 antibody or antigen-binding fragment thereof.

In preferred embodiments of the disclosed methods, uses and kits, the patient is treated with an IL-17 antibody or antigen-binding fragment thereof for at least 1 year.

In preferred embodiments of the disclosed methods, uses and kits, the patient has a rapid pain reduction as fast as one week after the first dose of IL-17 antibody or antigen-binding fragment thereof as measured by VAS or NRS.

In a preferred embodiment of the disclosed methods, uses and kits, the patient has a rapid CRP reduction as fast as 1 week after the first dose of IL-17 antibody or antigen-binding fragment thereof as measured using a standard CRP assay.

In preferred embodiments of the disclosed methods, uses and kits, the patient has a modified Sartorius score reduction at 16 weeks of treatment.

In preferred embodiments of the disclosed methods, uses and kits, the patient has an improvement of DLQI at 16 weeks of treatment.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is a monoclonal antibody.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is a human antibody.

In preferred embodiments of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment is a human monoclonal antibody.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is a human antibody of IgG ₁ subtype.

In a preferred embodiment, the IL-17 antibody or antigen-binding fragment thereof has a kappa light chain.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgG ₁ kappa type.

In preferred embodiments of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment has a T _max of about 7 to 8 days.

In preferred embodiments of the disclosed methods, uses and kits, the IL-17 antibody or antigen-binding fragment has an absolute bioavailability of about 60% to about 80%.

In a preferred embodiment of the invention, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

Kit

The present invention also encompasses kits for treating HS. Such kits include IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g. , IL-17 antibody or antigen-binding fragment thereof) (eg, in liquid or lyophilized form) or a pharmaceutical composition comprising an IL-17 antagonist (described above). Additionally, such kits may include means for administering an IL-17 antagonist (eg, autoinjector, syringe and vial, prefield syringe, prefield pen) and instructions for use. The kit is for treating, e.g., delivering HS in combination with an included IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab. (Described above). Such kits may also include instructions for administration of an IL-17 antagonist (eg, IL-17 antibody, eg secukinumab) to treat HS patients. These instructions are for use with an included IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab (e.g., 10 mg/kg, 300 mg, 450 mg), route of administration (e.g. IV, SC) and dosing regimen (e.g. weekly, monthly, weekly and subsequent months, weekly and every other biweekly, etc.).

The phrase “means for administration” is any use for systemic administration of a drug to a patient, including, but not limited to, prefilled syringes, vials and syringes, injection pens, autoinjectors, IV drips and bags, pumps, and the like. It is used to indicate possible execution. With this article, the patient can self-administer the drug (ie, administer the drug without the assistance of a physician), or the medical practitioner can administer the drug. In some embodiments, a total dose of 300 mg will be delivered in a total volume of 2 ml placed in 2 PFS or autoinjectors, each PFS or autoinjector being 150 mg/ml IL-17 antibody, e.g. Contains a volume of 1 ml with secuquinumab. In this case, the patient receives two 1 ml injections (multidose formulation). In a preferred embodiment, a total dose of 300 mg will be delivered in a total volume of 150 ml/ml of IL-17 antibody placed in a single PFS or autoinjector, eg 2 ml of secukinumab. In this case, the patient receives one 2 ml injection (single dose formulation).

IL-17 antagonists (e.g., IL-17 binding molecules, e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g. secukinumab) and means for administering IL-17 antagonists to HS patients Disclosed herein are kits for use in treating a patient with HS, including. In some embodiments, the kit further comprises instructions for the administration of an IL-17 antagonist, the instructions comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or antigen thereof) -Binding fragments, e.g. secukinumab) to the patient

1) SC administration at about 300 mg to about 450 mg (e.g., about 300 mg, or about 450 mg) every week for 0, 1, 2, and 3 weeks, after which

a) starting every 4 weeks every month (every 4 weeks); or

b) Starts for 4 weeks every other week (every 2 weeks)

SC administration at about 300 mg to about 450 mg (eg, about 300 mg, about 450 mg);

2) IV administration at about 3 mg/kg to about 10 mg/kg (e.g., about 3 mg/kg, about 10 mg/kg) every other week for 0, 2, and 4 weeks, followed by

a) starting every 8 weeks every month (every 4 weeks); or

b) starting every 6 weeks every other week (every 2 weeks)

Indicates that SC is administered at about 300 mg to about 450 mg (eg, about 300 mg, about 450 mg).

General Information

In the most preferred embodiment of the disclosed uses, methods and kits, the IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is a) a human comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 An IL-17 antibody or antigen-binding fragment thereof that binds to the epitope of IL-17; b) an IL-17 antibody or antigen-binding fragment thereof that binds to the epitope of human IL-17, including Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer with two mature human IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88 in one chain , Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains); d) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer with two mature human IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88 in one chain , Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, the IL-17 antibody or antigen-binding fragment thereof has a K _D of about 100 to 200 pM, and the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 23 days to about 35 days); e) IL-17 antibody that binds to the epitope of the IL-17 homodimer with two mature IL-17 protein chains (the epitope is Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, in one chain) Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, IL-17 antibody is about when K _D is measured by a biosensor system (e.g., Biacore ^® ). 100-200 pM, IL-17 antibody has an in vivo half-life of about 23 to about 30 days); And f) i) an immunoglobulin heavy chain variable domain (V _H ) comprising the amino acid sequence set forth in SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V _L ) comprising the amino acid sequence set forth in SEQ ID NO: 10; iii) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and an immunoglobulin V _L domain comprising the amino acid sequence set forth in SEQ ID NO: 10; iv) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; v) an immunoglobulin V _L domain comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; vi) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; vii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; viii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15; Or xi) an IL-17 antibody comprising an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15 or an antigen-binding fragment thereof.

In the most preferred embodiment of the disclosed method, kit or use, the IL-17 antibody or antigen-binding fragment thereof is a monoclonal antibody. In a most preferred embodiment of the disclosed method, kit or use, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody, preferably a human antibody. In the most preferred embodiment of the disclosed method, kit or use, the IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgG ₁ isotype. In the most preferred embodiment of the disclosed method, kit or use, the antibody or antigen-binding fragment thereof is secukinumab.

In the most preferred embodiment of the disclosed methods, kits or uses, the antibody or antigen-binding fragment thereof is secukinumab, the dose size is even (referred to as a “fixed” dose that is different from body weight based or body surface area based dosing), dose Is 300 mg, the route of administration is SC, and the regimen is 0 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc. (0 weeks, 1 week, 2 weeks and Dosing weekly for 3 weeks, then every 6 weeks starting every other week).

The details of one or more embodiments of the invention are set forth in the accompanying description. Although any methods and materials similar or identical to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described below. Other features, objects, and advantages of the invention will be apparent from the description and claims. In this specification and the appended claims, the singular form includes a plural reference unless the context clearly indicates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference. The following examples are presented to more fully illustrate preferred embodiments of the invention. This embodiment should not be construed in any way as limiting the scope of the disclosed subject matter as defined by the appended claims.

Example

Example 1: Initial study of anti-IL-17 antibodies in treating HS.

Initial clinical evidence of the effect of the anti-IL-17 antibody CJM112 supports the potential of anti-IL-17 antibody as an effective treatment for patients with HS. Like Secukinumab, CJM112 is a recombinant fully human anti-interleukin-17A monoclonal antibody of the IgG1/κ isotype developed for possible treatment of autoimmune and inflammatory diseases. CJM112 binds human homodimer IL-17A with higher affinity (6 pM) than secukinumab and neutralizes the biological activity of IL-17A in vitro.

This Phase 2 study (CCJM112X2202) was a randomized, placebo-controlled, double-blind, multicenter study with a period of 2 in patients with moderate to severe chronic HS in parallel groups conducted in the United States, Denmark, Switzerland, Germany and the Netherlands. . The study consisted of a screening period of approximately 4 weeks, two 16-week sequential treatment periods (Period 1 and Extended Period 2), and approximately 12 weeks of follow-up without treatment. Patients were randomized in a 2:1:1 ratio in one of three treatment sequences:

치료 순서 1: 기간 1에 CJM112 300 mg s.c.; 연장 기간 2에 위약 s.c.

Treatment sequence 1: CJM112 300 mg sc in Period 1; Placebo sc in extension period 2

치료 순서 2: 기간 1에 위약 s.c.; 연장 기간 2에 CJM112 50 mg s.c.

Treatment sequence 2: placebo sc in Period 1; CJM112 50 mg sc in extended period 2

치료 순서 3: 기간 1에 위약 s.c.; 연장 기간 2에 CJM112 300 mg s.c.

Treatment sequence 3: placebo sc in Period 1; CJM112 300 mg sc in extended period 2

During each treatment period, patients received a total of 10 doses. Study medication was administered subcutaneously (s.c.) in a clinical institution. The drug under investigation, 150 mg/ml CJM112 and coincident placebo were provided in glass vials containing 150 mg of CJM112 or placebo, respectively, as a liquid. In each treatment period, the first 5 doses were administered weekly, followed by the 5 doses every 2 weeks.

The primary endpoint chosen is the clinical response rate (based on responders defined as a 2-point reduction in the Pseudo Comprehensive Assessment (HS PGA) score-of purulent pyelonephritis from baseline). The HS-PGA score is a static comprehensive severity 6-point scale described in Kimball et al 2012 Ann Intern Med 157:846-855.

The study population undergoes previous antibiotic treatment, HS-PGA score of at least moderate severity (at least 3 on the 6-point scale) at baseline, at least 4 inflammatory abscesses present in at least 2 distinct anatomical sites, and/or Or adult male and female patients with chronic HS clinically diagnosed for at least one year (before screening), with inflammatory nodules (ANs) and at least one site must be at a minimum Hurley II stage (severity) at baseline lost. At baseline, no more than 25 drainage fistulas were permitted for eligibility.

In addition, the body weight needs to be 50 to 150 kg.

Exclusion criteria include previous treatment with biologics that block IL-17 or IL-17R, including secukinumab, ixekizumab and brodalumab, other biologics (e.g. adalimumab within the past 3 months) ), the use of any systemic treatment for HS in the last 4 weeks prior to randomization (e.g., retinoids or other immunomodulatory agents), or the use of systemic antibiotics for HS in the last week before randomization/first treatment Included. When spironolactone or other antiandrogens (eg finasteride, cyproterone acetate, etc.) are used (for HS), only patients who have a stable dose in the past 3 months and plan to continue during the study period are eligible. Exclude patients with a history of severe systemic candidiasis infection or evidence of candidiasis in the last 2 weeks prior to inclusion, and patients with active systemic or skin infections (other than cold or HS-related) for 2 weeks prior to randomization/first treatment Needs to be. No additional exclusion criteria were applied. Topical antibiotics and disinfectants, and standard wound healing were accepted throughout the study. Oral antibiotics may have been used as a remedy for skin infections, but should not be used longer than two weeks.

A total of 66 patients were enrolled and randomized to Period 1 (33 in the CJM112 300 mg group and 33 in the placebo group), of which 60 (90.9%) patients (29 in the CJM112 300 mg group and 29 in the placebo group) 31) completed from Period 1 to Week 16. A total of 6 patients discontinued the study 16 weeks ago. Reasons for discontinuation of the study were "trace tracking failure", "side effects" (cystitis in the CJM112 group) and "patient/guardian determination".

The primary endpoint was to determine the efficacy of 300 mg CJM112 in HS patients using clinical response rates at 16 weeks (end of Period 1) compared to placebo. The HS-PGA (Pulmonary Hysteritis-Pseudo-General Assessment, Kimball 2012) response rate, defined as a reduction of at least 2 points from baseline on the 6-point scale, was used for that purpose.

The HS-PGA response rate is shown in Figure 1 , and Bayesian statistics were used to compare treatments at 16 weeks ( Table 4 ).

Percentage of patients reaching this endpoint at Week 16 (HS-PGA response rate) were 32.3% of responders (or 10 of 31) for anti-IL17 treatment compared to 12.5% (or 4 of 32) for placebo. It was. The posterior probability for CJM112 is as high as 0.97, indicating that this can reflect the true effect.

The primary endpoint of this study was slightly different from the primary endpoint of a phase 2 study previously conducted using HUMIRA (Kimball et al 2012 Ann Intern Med 157:846-855). The same 6-point HS-PGA score was used, but the definition of responders differed from study to study. Kimball used a more rigorous and complex definition, where a two-point reduction from baseline and a clean/minimum/slight step at week 16 were necessary to achieve responder status.

For comparison purposes, we calculated response rate scores by the definition of "Kimball 2012". Six out of 31 patients (19.4%) responded in the CJM112 group, and only two out of 32 (6.3%) responded in the placebo-treated group. This is comparable to what adalimumab achieved in a phase 2 study ( Table 5 ).

In addition to the primary endpoint (HS-PGA), a reduction in the level of inflammatory lesions, mainly in inflammatory nodules, was observed in both the CJM112 and placebo treated arms, and decreased to a higher scale in the CJM112 group. The magnitude of the therapeutic effect was similar to that observed with adalimumab (-2.6 inflammatory lesions in CJM112 compared to placebo versus -2.4 to -3.0 in adalimumab compared to placebo). However, the therapeutic effect in reducing inflammatory lesions was not statistically significant in this small phase 2 study.

To better understand the clinical relevance of the effect on the number of inflammatory lesions observed in the CJM112 Phase 2 study, the data were compared to data available to the public from adalimumab ( Table 6 ). Absolute lesion number results are only available to the public from Phase 3 studies. PIONEER 1 recruited a more severe population closer to the CJM112 phase 2 study than PIONEER 2, and therefore PIONEER 1 was used for the following comparison.

Although the population of the CJM112 Phase 2 study had a greater number of inflammatory lesions at baseline than the PIONEER 1 study, the magnitude of the change observed in the number of inflammatory lesions during the study was similar between the placebo groups in both studies, so that phase II of CJM112 was It is supported that the entered population represents moderate to severe HS populations who acted within the variability estimated during the study.

The therapeutic effect on adalimumab and CJM112 was mainly observed in the number of inflammatory lesions, and was slightly higher on CJM112 than adalimumab. Only small therapeutic effects were observed in abscesses and drainage fistulas in both studies. Consistent results were also observed in PIONEER 2 (Kimball et al 2016a N Engl J Med; 375(5):422-434.).

No significant clinical safety signal was observed despite the use of a relatively high dose of IL-17 blockade (the first 5 CJM112 300 mg doses were administered weekly, followed by 5 biweekly administrations). Most AEs were moderate to mild or moderate. Some infections (eg, nasopharyngitis, upper respiratory tract infection, cystitis) were more frequent in CJM112 treated patients, but the overall infection was the same frequency in the active group than in the placebo treated group. On the other hand, side effects have frequency differences between groups, and a small number of patients are not allowed to end up in this fairly small group. Serious side effects were observed only during the placebo treated period and were considered unrelated (angina and abscess). The latter appeared approximately 23 weeks after the last dose of CJM112 and was hospitalized for removal of HS abscess.

No new or unexpected safety signals were detected in the HS population after treatment with the high affinity anti-IL-17A antibody CJM112.

Example 2:

Example 2A: Prediction of response rates in heavy subjects with higher doses of secukinumab (450 mg) and more frequent doses (Q2w)

The purpose of the modeling and simulation (M&S) work in this example is to investigate the simulated efficacy of secukinumab in heavy subjects after the two higher dose regimens mentioned above, 450 Q4W and 300 Q2W. The inventors here used a standard dose for secukinumab in psoriasis compared to the predicted response using a higher dose regime, i.e. 450 mg Q4W or 300 mg Q2W, i.e. in patients weighing 90 kg or more using 300 mg Q4W. Report the modeling and simulation (M&S) work that investigated the reaction rates of PASI 75 and PASI 90. The main purpose of the task is to use model predicted (ie, simulated) response rates to estimate the extent of improvement by higher doses in heavier patients.

PASI data from studies CAIN457A2302 and CAIN457A2303 up to week 52 were used for this analysis. Only subjects over 90 kg were used to build the model (n = 641). Data included responses from both 150 mg and 300 mg regimens in addition to patients initially treated with placebo up to 12 weeks and subsequently randomized to 150 mg or 300 mg. Response variables, either PASI 75 or PASI 90, binary results were modeled as a function of serum secukinumab concentration. Due to the lag time between reaction and concentration, an indirect reaction model was used. All measurements up to week 52 were used in the model. The predicted concentrations were used at PASI measurement times calculated from post estimates of the previously developed Secukinumab Population Pharmacokinetic (PK) model.

Briefly, the model was a two-compartment model by weight and primary absorption as a covariate for median clearance (CL), median and peripheral compartment volumes (V2 and V3), and inter-compartment clearance (Q). Post estimates for PK model parameters for patients in A2302 and A2303 were used as inputs to pharmacokinetic (PD) modeling. Previous modeling effects on secukinumab in psoriasis also included a population PK/PD model for continuous PASI scores. However, this model has some limitations in describing the PASI 75 response rate (e.g., some over-prediction during the induction phase), which is more pronounced by more extreme response limits such as PASI 90. Covariate investigations (eg, baseline PASI or body weight) were also previously investigated and found to not improve model fit, and therefore covariate investigations were not performed here.

The two components of the population model are as follows: a structural model in the data and, to the extent possible, a structural model describing the mechanism that produces this trend; And a random effects model that describes inter-subject and intra-subject variability for this trend. In this analysis, model components are selected and assembled based on a combination of prior knowledge, modeling experience by PASI response of secukinumab, and data processing decisions supported by statistical and empirical rules. Analysis was performed using a NONMEM software system, NONMEM version 7.3.0 (Icon Development Solutions, Ellicott City, MD) using a MODESIM high performance computing environment connected from GPSII. Perl-speaks-NONMEM 4.2.0 was used to automate execution. All model building was performed using the Laplace method. Analysis was performed to estimate population parameters (mean and inter-subject variability).

After investigation of model diagnostics, the final (best) model was selected based on likelihood and Bayesian Information Criteria (BIC). Using the best model, simulations were used to predict PASI 75 or PASI 90 response rates. For each regimen (ie, 300 mg Q4W, 300 mg Q2W, and 450 mg Q4W), 1000 replicates were generated using the NONMEM ONLYSIMULATION option. Mock was generated using fixed effect parameters (ie, emax, ec50, kout, gamma and alpha) and final estimates of variability between sampling individuals. PASI 75 or PASI 90 binary responses were simulated by sampling from the binary distribution with probability determined from the model. The source dataset for the mock was the same dataset used to establish the model, ie using subjects weighing more than 90 kg and including the subject's post-PK estimates. Regular dosing schedules for 300 mg Q4W, 300 mg Q2W and 450 mg Q4W (once a week up to 4 weeks and then every 4 weeks for Q4W up to 52 weeks or every 2 weeks for Q2W) are regular sampling schedules, That is, it was included in the mock dataset once every week until 12 weeks and after every 4 weeks thereafter. The predicted response rates were calculated for each simulated replicate and at each time point. From 1000 runs, median and 95% predicted intervals for response rates were determined.

FIG. 2 shows the simulated PASI 90 response rate for different regimens in subjects weighing 90 kg or more. Table 7 contains the predicted response rates for PASI 75 and PASI 90 at 12, 16 and 52 weeks for different regimens.

The simulation predicts that a higher response rate (for PASI 75 or PASI 90) in heavy subjects will be followed by a higher dose regime, 300 mg Q2W or 450 mg Q4W compared to the standard 300 mg Q4W regimen. The simulation suggests that the response rate at Week 16 will be similar for the higher dosing regimen (91% for PASI 75 and 76% for PASI 90, see Table 7 ). However, compared to 450 mg Q4W, the 300 mg Q2W regimen is expected to produce a higher response rate starting from 20 weeks. The median response rate after 300 mg Q2W versus 450 mg Q4W at week 52 is predicted to be 99% vs. 96% for PASI 75 and 93% vs. 87% for PASI 90 (see Table 7 ).

Based on this information, it is expected that HS patients who are more likely to be heavier patients and have deep tissue disease will benefit from higher doses of secukinumab or higher doses of secukinumab.

Example 2B: Secukinumab dose-response modeling and simulation for heavy patients

Modeling and simulation in this example consist of 52 weeks of data from the Secukinumab OPTIMIZE study. OPTIMIZE (NCT02409667) is a 52-week comparative, randomized, multicenter, open-ended evaluation with a blinded assessment to evaluate the efficacy, safety and tolerability of secukinumab 300 mg SC in long-term treatment optimization in patients with moderate to severe chronic plaque psoriasis -It was a label experiment. In this study, patients who reached the suboptimal responder at 24 weeks, that is, PASI75 (i.e., 75% reduction in PASI score from baseline), but did not reach PASI90 after 24 weeks under secukinumab 300 mg q4w, aged up to 52 weeks Cookienumab 300 mg q4w or secukinumab 300 mg q2w was randomized following.

The top panel of FIG. 5 shows the percentage of responders (patients who achieved PASI90, ie a 90% reduction in PASI score at week 52 from baseline at 90% reduction) by treatment group (q2w or q4w) and weight classification in that subgroup (90 less than kg or more than 90 kg). The lower panel shows the lowest concentration of secukinumab (given in mcg/mL) at week 52 in the same subgroup.

Simulations show that heavier patients (>90 kg) benefit from 300 mg Q2W dosing in terms of efficacy as well as in terms of exposure. The PASI% response shows improved efficacy in patients with higher antibody concentrations greater than 90 kg. However, this is not seen in patients weighing less than 90 kg. The data suggest that efficacy in patients with psoriasis is maximized above about 30 mcg/mL (PASI 90%-60%). Based on this information, it is expected that HS patients who are more likely to be heavier patients and have deep tissue disease will benefit from the more frequent administration of secukinumab.

Example 3: Efficacy and safety of secukinumab in adult patients with moderate to severe HS.

Table 8 below details the design of clinical trials to demonstrate the efficacy of two secukinumab dose regimes compared to placebo by evaluating the proportion of subjects who achieved HiSCR after 16 weeks of treatment.

In addition to the regimen using weekly induction dosing, followed by every 4 weeks (Q4W) maintenance dosing, we used Q2W maintenance regimes to achieve higher exposures than the therapeutic regimens commonly used in the treatment of plaque psoriasis for the following reasons: will be:

통상적인 건선 집단과 비교하여 HS를 갖는 환자 집단에 더 높은 체중이 기대되어(HS 집단에 대략 10 kg 더 무거운 체중)(Kimball et al (2016) N Engl J Med; 375(5):422-434), 적절한 노출을 달성하기 위해 더 높은 용량을 잠재적으로 요한다. 전신 노출은 상대성장 관계로 체중에 따라 달라진다. 세쿠키누맙 청소율에 대해, 상대성장 지수가 1에 가까운 것으로 추정되고; 다른 말로, 체중의 배가는 청소율을 거의 2배 증가시키고, 따라서 혈청 노출을 감소시킨다(Bruin et al (2017) J Clin Pharmacol 57(7):876-885). 따라서, 건선 섭생으로 생긴 것보다 더 높은 노출에 의한 세쿠키누맙 투약 섭생의 평가는 HS 환자 집단에서 적절하다.

Higher weight was expected (approximately 10 kg heavier weight for the HS population) in the patient population with HS compared to the normal psoriasis population (Kimball et al (2016) N Engl J Med; 375(5):422-434 ), potentially requiring higher doses to achieve proper exposure. Systemic exposure depends on body weight in a relative growth relationship. For the secuquinumab clearance rate, the relative growth index is estimated to be close to 1; In other words, doubling body weight almost doubles the clearance rate and thus reduces serum exposure (Bruin et al (2017) J Clin Pharmacol 57(7):876-885). Therefore, evaluation of the secukinumab dosing regimen with higher exposure than that resulting from the psoriasis regimen is appropriate in the HS patient population.

건선에서보다 더 높은 국소 피부 노출은 심부 염증성 피부 병변을 갖는 이 질병에 필요할 것이다.

Higher local skin exposure than in psoriasis will be necessary for this disease with deep inflammatory skin lesions.

HS에서의 아달리무맙(HUMIRA®)에 의한 임상 경험은 건선에서보다 HS에서 더 높은 노출을 갖는 투약 섭생을 지지한다.

Clinical experience with adalimumab (HUMIRA®) in HS supports a dosing regimen with higher exposure in HS than in psoriasis.

결정적으로 도 4로부터 볼 수 있는 것처럼, 본 발명자들은 동일한 유도 기간 이후에 첫달 동안에 4주 유지 간격에 의해 달성되는 것보다 줄어든 유지 용량 간격(2주마다)을 사용하여 세쿠키누맙에 대한 상당히 더 높고 더 일관된 전신 노출을 달성할 수 있다는 것을 결정하였다. 용량 발견 전략은 도 5에 의해 더 지지되고, 이 도면은 약 30 mcg/mL 세쿠키누맙 최저 농도 초과에서 건선 환자에서의 효능이 최대화된다(PASI 90% 내지 60%)는 것을 보여준다.

Crucially, as can be seen from FIG. 4 , the inventors are significantly higher for secukinumab using a reduced maintenance dose interval (every 2 weeks) than is achieved by the 4 week maintenance interval during the first month after the same induction period. It was determined that a more consistent systemic exposure could be achieved. The dose discovery strategy is further supported by Figure 5 , which shows that efficacy is maximized (PASI 90%-60%) in patients with psoriasis above about 30 mcg/mL secukinumab minimum concentrations.

SEQUENCE LISTING <110> Novartis AG Loesche, Christian de Vera Ju?ez, Ana Mar? Bruin, Gerard Ezzet, Farkad <120> METHODS OF TREATING HIDRADENITIS SUPPURATIVA USING IL-17 ANTAGONISTS <130> PAT057938 FF <140> Herewith <141> Herewith <150> 62/588687 <151> 2017-11-20 <160> 20 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> artificial <220> <223> CDR1 = hypervariable region 1 of heavy chain of AIN457 <400> 1 Asn Tyr Trp Met Asn 1 5 <210> 2 <211> 17 <212> PRT <213> ARTIFICIAL <220> <223> CDR2 = hypervariable region 2 of heavy chain of AIN457 <400> 2 Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val Lys 1 5 10 15 Gly <210> 3 <211> 18 <212> PRT <213> ARTIFICIAL <220> <223> CDR3 = hypervariable region 3 of heavy chain of AIN457 <400> 3 Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp Tyr Phe 1 5 10 15 Asp Leu <210> 4 <211> 12 <212> PRT <213> ARTIFICIAL <220> <223> CDR1' = hypervariable region 1 of light chain of AIN457 <400> 4 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 5 <211> 7 <212> PRT <213> ARTIFICIAL <220> <223> CDR2' = hypervariable region 2 of light chain AIN457 <400> 5 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 6 <211> 9 <212> PRT <213> ARTIFICIAL <220> <223> CDR3' = hypervariable region 3 of light chain AIN457 <400> 6 Gln Gln Tyr Gly Ser Ser Pro Cys Thr 1 5 <210> 7 <211> 381 <212> DNA <213> HOMO SAPIENS <220> <221> CDS <222> (1)..(381) <400> 7 gag gtg cag ttg gtg gag tct ggg gga ggc ttg gtc cag cct ggg ggg 48 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt agt aac tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 tgg atg aac tgg gtc cgc cag gct cca ggg aaa ggg ctg gag tgg gtg 144 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 gcc gcc ata aac caa gat gga agt gag aaa tac tat gtg ggc tct gtg 192 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 ctg caa atg aac agc ctg aga gtc gag gac acg gct gtg tat tac tgt 288 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gtg agg gac tat tac gat att ttg acc gat tat tac atc cac tat tgg 336 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 tac ttc gat ctc tgg ggc cgt ggc acc ctg gtc act gtc tcc tca 381 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 8 <211> 127 <212> PRT <213> HOMO SAPIENS <400> 8 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 9 <211> 327 <212> DNA <213> HOMO SAPIENS <220> <221> CDS <222> (1)..(327) <400> 9 gaa att gtg ttg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 atc tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ccg 288 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 tgc acc ttc ggc caa ggg aca cga ctg gag att aaa cga 327 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105 <210> 10 <211> 109 <212> PRT <213> HOMO SAPIENS <400> 10 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105 <210> 11 <211> 10 <212> PRT <213> artificial <220> <223> CDR1-x = hypervariable domain x of heavy chain of AIN457 <400> 11 Gly Phe Thr Phe Ser Asn Tyr Trp Met Asn 1 5 10 <210> 12 <211> 11 <212> PRT <213> artificial <220> <223> CDR2-x = hypervariable domain of heavy chain x of AIN457 <400> 12 Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr 1 5 10 <210> 13 <211> 23 <212> PRT <213> ARTIFICIAL <220> <223> CDR3-x = hypervariable domain x of heavy chain AIN457 <400> 13 Cys Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr 1 5 10 15 Trp Tyr Phe Asp Leu Trp Gly 20 <210> 14 <211> 215 <212> PRT <213> homo sapiens <400> 14 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 15 <211> 457 <212> PRT <213> homo sapiens <400> 15 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 130 135 140 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 195 200 205 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 210 215 220 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 16 <211> 7 <212> PRT <213> Homo sapiens <400> 16 Gln Ser Val Ser Ser Ser Tyr 1 5 <210> 17 <211> 3 <212> PRT <213> homo sapiens <400> 17 Gly Ala Ser One <210> 18 <211> 8 <212> PRT <213> homo sapiens <400> 18 Gly Phe Thr Phe Ser Asn Tyr Trp 1 5 <210> 19 <211> 8 <212> PRT <213> homo sapiens <400> 19 Ile Asn Gln Asp Gly Ser Glu Lys 1 5 <210> 20 <211> 20 <212> PRT <213> homo sapiens <400> 20 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 1 5 10 15 Tyr Phe Asp Leu 20

Claims (46)

As a method of treating purulent cholineitis (HS), a dose of about 300 mg to about 450 mg of IL every week for 0 weeks, 1 week, 2 weeks and 3 weeks for patients in need of treatment Administering a -17 antibody or antigen-binding fragment thereof subcutaneously (SC), followed by SC administration at a dose of about 300 mg to about 450 mg every other week (every two weeks) starting for 4 weeks;
IL-17 antibody or antigen-binding fragment thereof,
Iv) an immunoglobulin V _H domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and an immunoglobulin V _L domain comprising the amino acid sequence set forth in SEQ ID NO: 10;
Ii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 domain; or
Iii) an immunoglobulin V _H domain comprising the hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V _L comprising the hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Domains;
The IL-17 antibody or antigen-binding fragment thereof binds to an epitope of the IL-17 homodimer having two mature IL-17 protein chains, the epitope being Leu74, Tyr85, His86, Met87, Asn88, Val124 in one chain , Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 in other chains, IL-17 antibody has a K _D of about 100 to 200 as measured by a biosensor system. pM, and the IL-17 antibody has a half-life in vivo of about 23 days to about 30 days. The method of claim 1, wherein the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg or about 450 mg. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered SC at a dose of about 300 mg every week for 0 weeks, 1 week, 2 weeks, and 3 weeks, after which it starts for 4 weeks and then every other week. A method comprising administering SC at a dose of about 300 mg (every two weeks). (delete) The patient according to any one of claims 1 to 4, wherein the patient has an inflammatory lesion count after 1 year of treatment, a purulent psoriatic inflammatory disease clinical response (HiSCR: Hidradenitis Suppurativa Clinical Response), a Numerical Rating Scale (NRS). , Modified Sartorius HS score, purulent psoriasis-Hidradenitis Suppurativa-Physician Global Assessment (HS-PGA), or Dermatology Life Quality Index (DLQI) A method of achieving a sustained response when measured. The method of any one of claims 1 to 5, wherein the patient achieves a sustained response as measured by simplified HiSCR (sHiSCR) after one year of treatment. The method of any one of claims 1 to 6, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient has been previously treated with a systemic agent for HS. The method of claim 7, wherein the systemic agent is selected from the group consisting of topical treatment, antibiotics, immune system inhibitors, TNF-alpha inhibitors, IL-1 antagonists, and combinations thereof. The method of any one of claims 1 to 8, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient has never been treated with systemic or topical treatment for HS in the past. The method of any one of claims 1 to 9, wherein the IL-17 antibody or antigen-binding fragment is administered in combination with at least one of a TNF-alpha inhibitor, an antibiotic, an IL-1 inhibitor, or an immunosuppressant. The method of claim 1, wherein the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg. The method of any one of claims 1, 2, and 5-10, wherein the dose of the IL-17 antibody or antigen-binding fragment is about 450 mg. The method of claim 1, wherein the patient has moderate to severe HS. The method of claim 1, wherein the patient is an adult. 15. The method of any one of claims 1-14, wherein the patient is an adolescent. 16. The method of any one of claims 1 to 15, wherein the IL-17 antibody or antigen-binding fragment is placed in a pharmaceutical formulation, the pharmaceutical formulation further comprising a buffer and a stabilizer. 17. The method of any one of claims 1 to 16, wherein the pharmaceutical formulation is in liquid form. 18. The method of any one of claims 1 to 17, wherein the pharmaceutical formulation is in lyophilized form. 19. The method of any one of claims 1 to 18, wherein the pharmaceutical formulation is placed in a pre-filled syringe, vial, injection pen or autoinjector. The dosage of any one of claims 1 to 19, wherein the dose of the IL-17 antibody or antigen-binding fragment is about 300 mg, and the pharmaceutical formulation is selected from the group consisting of prefilled syringes, injection pens and autoinjectors. Wherein the means is disposed in a kit, the kit further comprising instructions for use. The dose of IL-17 antibody or antigen-binding fragment according to any one of claims 1 to 20, wherein the dosage is about 300 mg, and the pharmaceutical formulation is placed in an autoinjector or prefield syringe, wherein the autoinjector or pre-injector. The field syringe is placed in a kit, the kit further comprising instructions for use. 22. The method of any one of claims 1 to 21, wherein the dose of IL-17 antibody or antigen-binding fragment is about 300 mg, and the pharmaceutical formulation is placed in an autoinjector or prefield syringe, wherein the autoinjector or free The field syringe is placed in a kit, the kit further comprising instructions for use. 23. The method of any one of claims 1 to 22, wherein the dose of IL-17 antibody or antigen-binding fragment is about 450 mg, and the pharmaceutical formulation is placed in an autoinjector or prefield syringe, wherein the autoinjector or free The field syringe is placed in a kit, the kit further comprising instructions for use. 24. The dose of any one of claims 1 to 23, wherein the dose is administered in a single subcutaneous dose in a total volume of 2 ml from a formulation comprising 150 mg/ml of the IL-17 antibody or antigen-binding fragment. , And the patient's pharmacological exposure to an IL-17 antibody or antigen-binding fragment is a patient for an IL-17 antibody or antigen-binding fragment using two separate subcutaneous doses of a total volume of 1 ml each of the same formulation. Equivalent to pharmacological exposure, method. 24. The dose of any one of claims 1 to 3 and 5 to 23, wherein the dose is in a volume of 1 ml each from a formulation comprising 150 mg/ml of the IL-17 antibody or antigen-binding fragment. The method, which is 300 mg administered in two separate subcutaneous administrations. 26. The method of any one of claims 1-25, wherein the IL-17 antibody or antigen-binding fragment has a T _max of about 7 to 8 days. 27. The method of any one of claims 1 to 26, wherein the IL-17 antibody or antigen-binding fragment has an absolute bioavailability of about 60% to about 80%. 28. The method of any one of claims 1 to 27, wherein the IL-17 antibody or antigen-binding fragment is a human monoclonal antibody. The method of any one of claims 1 to 28, wherein the IL-17 antibody or antigen-binding fragment is of the IgG ₁ /kappa isotype. 30. The method of any one of claims 1 to 29, prior to treatment with the IL-17 antibody or antigen-binding fragment, the patient has an HS-PGA score of 3 or higher. 31. The method of any one of claims 1 to 30, prior to treatment with an IL-17 antibody or antigen-binding fragment, the patient is classified as a Hurley II or III stage. 32. The method of any one of claims 1 to 31, wherein the patient achieves simplified HiSCR at 16 weeks of treatment. 33. The method of any one of claims 1 to 32, wherein the patient achieves NRS30 at 16 weeks of treatment. 34. The method of any one of claims 1 to 33, wherein the patient has a decrease in HS exacerbation at 16 weeks of treatment. The method of any one of claims 1 to 34, wherein the patient achieves a reduction of 6 or less as measured by DLQI at 16 weeks of treatment. 36. The method of any one of claims 1 to 35, wherein when the method is used to treat a population of patients with moderate to severe HS, at least 51% of the patients respond to the dosing phase at 16 weeks of treatment. How to achieve simplified HiSCR. 37. The method of any one of claims 1 to 36, wherein when the method is used to treat a population of patients with moderate to severe HS, at least 40% of the patients respond to the dosing phase at 16 weeks of treatment. How to achieve NRS30 reaction. The method of any one of claims 1 to 37, wherein when the method is used to treat a population of patients with moderate to severe HS, less than 15% of the patients respond during the 16-week treatment in response to the administration step. How to experience HS exacerbations. The method of any one of claims 1 to 38, prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient does not have extensive scarring as a result of HS (fistula less than 20). The method of any one of claims 1 to 39, wherein the patient is further treated with at least one topical agent and at least one disinfectant in combination with an IL-17 antibody or antigen-binding fragment thereof. The method of any one of claims 1-40, wherein the patient is treated with an IL-17 antibody or antigen-binding fragment thereof for at least 1 year. The method of any one of claims 1 to 41, wherein the patient has rapid pain reduction as fast as 1 week after the first dose of IL-17 antibody or antigen-binding fragment thereof as measured by VAS or NRS. . The method of any one of claims 1 to 42, wherein the patient has a rapid CRP reduction as fast as one week after the first dose of IL-17 antibody or antigen-binding fragment thereof as measured by a standard CRP assay. . The method of any one of claims 1 to 43, wherein the patient has a reduction in modified Sartorius score at 16 weeks of treatment. The method of any one of claims 1 to 44, wherein the patient has an improvement in DLQI at 16 weeks of treatment. 46. The method of any one of claims 1 to 45, wherein the IL-17 antibody or antigen-binding fragment is secukinumab.

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